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  1. Test Catalog
  2. Invitae Common Hereditary Cancers Panel

Invitae Common Hereditary Cancers Panel

Test description

The Invitae Common Hereditary Cancers Panel analyzes 47 genes associated with cancers of the breast, ovary, uterus, prostate, and gastrointestinal system, which includes the stomach, colon, rectum, small bowel, and pancreas. The panel is designed to maximize diagnostic yield for individuals with a personal or family history of mixed cancers affecting these organ systems.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Genes tested

APC ATM AXIN2 BARD1 BMPR1A BRCA1 BRCA2 BRIP1 CDH1 CDK4 CDKN2A CHEK2 CTNNA1 DICER1 EPCAM GREM1 HOXB13 KIT MEN1 MLH1 MSH2 MSH3 MSH6 MUTYH NBN NF1 NTHL1 PALB2 PDGFRA PMS2 POLD1 POLE PTEN RAD50 RAD51C RAD51D SDHA SDHB SDHC SDHD SMAD4 SMARCA4 STK11 TP53 TSC1 TSC2 VHL

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Primary panel (47 genes)

APC ATM AXIN2 BARD1 BMPR1A BRCA1 BRCA2 BRIP1 CDH1 CDK4 CDKN2A CHEK2 CTNNA1 DICER1 EPCAM GREM1 HOXB13 KIT MEN1 MLH1 MSH2 MSH3 MSH6 MUTYH NBN NF1 NTHL1 PALB2 PDGFRA PMS2 POLD1 POLE PTEN RAD50 RAD51C RAD51D SDHA SDHB SDHC SDHD SMAD4 SMARCA4 STK11 TP53 TSC1 TSC2 VHL

Panel details and technical assay limitations

Clinical information

  • ataxia-telangiectasia (A-T)
  • constitutional mismatch repair deficiency (CMMR-D)
  • Cowden and Cowden-like syndrome
  • DICER1 syndrome
  • familial adenomatous polyposis (FAP)
  • familial gastrointestinal stromal tumors (GIST)
  • Fanconi anemia
  • hereditary breast and ovarian cancer syndrome (HBOC)
  • hereditary diffuse gastric cancer (HGDC)
  • juvenile polyposis syndrome (JPS)
  • Li-Fraumeni syndrome (LFS)
  • Lynch syndrome – also known as hereditary non-polyposis colorectal cancer (HNPCC)
  • melanoma-pancreatic cancer syndrome (M-PCS)
  • multiple endocrine neoplasia type 1 (MEN1)
  • MUTYH-associated polyposis (MAP)
  • neurofibromatosis type 1 (NF1)
  • Nijmegen breakage syndrome (NBS)
  • oligodontia-colorectal cancer syndrome
  • Peutz-Jeghers syndrome (PJS)
  • rhabdoid tumor predisposition syndrome (RTPS)
  • tuberous sclerosis complex (TSC)
  • von Hippel-Lindau syndrome (VHL)

The Invitae Common Hereditary Cancers panel analyzes 47 genes associated with hereditary breast, ovarian, uterine, prostate, colorectal, gastric, melanoma, and pancreatic cancers. Individuals with a pathogenic variant in one of these genes have an increased risk of developing certain cancers, many of which may be difficult both to detect and to treat. Identifying those at high risk enables implementation of additional screening, surveillance, and interventions. These efforts may result in risk-reduction and early diagnosis, increasing the chances of successful treatment and survival.

Breast cancer: The average woman’s lifetime risk of developing breast cancer is 12%. Although there are a number of other genes associated with hereditary breast cancer, hereditary breast and ovarian cancer syndrome (HBOC) due to pathogenic variants in BRCA1 and BRCA2 accounts for most cases in individuals with a strong family history or an early-onset diagnosis.

Ovarian: The general population risk for ovarian cancer is 1.3%. Lynch syndrome and hereditary breast and ovarian cancer syndrome (HBOC) due to pathogenic variants in the BRCA1 and BRCA2 genes are common causes of inherited ovarian cancer, as are several other hereditary cancer genes.

Uterine: The general population risk for uterine cancer is 2.7%. Lynch syndrome is the most common inherited cause of uterine cancer, although there are a number of other hereditary cancer genes associated with this cancer type.

Prostate: A man’s lifetime risk for developing prostate cancer is 1 in 7 (15%). Inherited pathogenic variants in certain genes — particularly ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PMS2, and TP53 — account for some cases of hereditary prostate cancer. Men with pathogenic variants in these genes have an increased risk of developing prostate cancer and, in some cases, other cancers as well.

Colorectal: Colorectal cancer (CRC) is the third-most-common cancer diagnosis in the United States. Hereditary colorectal cancer syndromes are generally divided into two types, Lynch syndrome and polyposis syndromes. Lynch syndrome, also called hereditary non-polyposis colon cancer (HNPCC), is caused by pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM and is the most common inherited cause of colorectal cancer. Polyposis syndromes are characterized by the development of numerous precancerous polyps, which may become malignant.

Gastric: Gastric cancer occurs in approximately 1 in 93 individuals in the general population. Gastric adenocarcinomas account for 90%-95% of gastric cancers and are further histologically divided into intestinal type and diffuse type. The most common cause of hereditary gastric cancer is a pathogenic variant in CDH1, which causes hereditary diffuse gastric cancer syndrome, but there are a number of other genes associated with an increased risk for gastric tumors. Gastrointestinal stromal tumors (GISTs) are characterized as sarcomas and are rare tumors of the GI tract that account for 1%-3% of all gastric cancers. The Invitae Common Hereditary Cancers panel includes genes that increase risk for each of these types of gastric tumors.

Pancreatic: There are two main types of pancreatic cancer: cancer of the exonic pancreas (pancreatic adenocarcinoma), which accounts for 95% of pancreatic tumors, and pancreatic neuroendocrine tumors. Hereditary pancreatic cancer can be caused by BRCA2 and CDKN2A, as well as by several other genes. The Invitae Common Hereditary Cancers panel analyzes the genes that are most commonly associated with an increased risk for both types of pancreatic cancer.

Melanoma: Most cases of melanoma are isolated and sporadic. The number of individuals who have an inherited risk of melanoma is unknown, but it is thought to be low. Most heritable cases are due to pathogenic variants in the CKDN2A gene as well as several other genes.

Individuals with a pathogenic variant identified by the Invitae Common Hereditary Cancers Panel have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial.

For gene-associated cancer risks, download our Cancer risk poster.

All of the genes on this panel have autosomal dominant inheritance for hereditary cancer predisposition. Several of these genes also have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions:

  • BRCA2, BRIP1, FANCC, PALB2, and RAD51C are associated with Fanconi anemia.
  • ATM and MRE11A are associated with ataxia-telangiectasia and ataxia-telangiectasia-like disorder (ATLD), respectively.
  • MLH1, MSH2, PMS2, and MSH6 are associated with constitutional mismatch repair deficiency (CMMR-D).
  • MUTYH is associated with MUTYH-associated polyposis (MAP).
  • MSH3 is associated with MSH3-associated polyposis.
  • NTHL1 is associated with NTHL1-associated polyposis.
  • NBN and RAD50 are associated with Nijmegen breakage syndrome and Nijmegen breakage syndrome-like disorder (NBSLD), respectively.

This panel may be considered for individuals with:

  • a clinical history indicative of a hereditary cancer syndrome but a limited pedigree due to small family size or adoption
  • a family history presenting with multiple cancer types that could fit the features of more than one hereditary cancer syndrome

There are also some common general features suggestive of a family with hereditary cancer syndrome. These include:

  • cancer diagnosed at an unusually young age
  • different types of cancer that have occurred independently in the same person
  • cancer that has developed in both organs of a set of paired organs (e.g., both kidneys, both breasts)
  • several close blood relatives that have the same type of cancer
  • unusual cases of a specific cancer type (e.g., male breast cancer)

  1. De, Brakeleer, S, et al. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum. Mutat. 2010; 31(3):E1175-85. doi: 10.1002/humu.21200. PMID: 20077502
  2. Chow, E, Macrae, F. A review of juvenile polyposis syndrome. J. Gastroenterol. Hepatol. 2005; 20(11):1634-40. doi: 10.1111/j.1440-1746.2005.03865.x. PMID: 16246179
  3. Kohlmann, W, Gruber, SB. Lynch Syndrome. 2004 Feb 05. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390
  4. Tan, MH, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 2012; 18(2):400-7. doi: 10.1158/1078-0432.CCR-11-2283. PMID: 22252256
  5. van, der, Post, RS, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J. Med. Genet. 2015; 52(6):361-74. doi: 10.1136/jmedgenet-2015-103094. PMID: 25979631
  6. Steffen, J, et al. Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int. J. Cancer. 2004; 111(1):67-71. doi: 10.1002/ijc.20239. PMID: 15185344
  7. Antoniou, AC, et al. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med. 2014; 371(6):497-506. doi: 10.1056/NEJMoa1400382. PMID: 25099575
  8. Heikkinen, K, et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis. 2006; 27(8):1593-9. doi: 10.1093/carcin/bgi360. PMID: 16474176
  9. Palles, C, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 2013; 45(2):136-44. PMID: 23263490
  10. Bellido, F, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.75. PMID: 26133394
  11. Walsh, T, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc. Natl. Acad. Sci. U.S.A. 2011; 108(44):18032-7. doi: 10.1073/pnas.1115052108. PMID: 22006311
  12. Meindl, A, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Genet. 2010; 42(5):410-4. PMID: 20400964
  13. Ahmed, M, Rahman, N. ATM and breast cancer susceptibility. Oncogene. 2006; 25(43):5906-11. doi: 10.1038/sj.onc.1209873. PMID: 16998505
  14. Breast, Cancer, Linkage, Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 1999; 91(15):1310-6. doi: 10.1093/jnci/91.15.1310. PMID: 10433620
  15. Maher, ER, et al. von Hippel-Lindau disease: a clinical and scientific review. Eur. J. Hum. Genet. 2011; 19(6):617-23. doi: 10.1038/ejhg.2010.175. PMID: 21386872
  16. Damiola, F, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast Cancer Res. 2014; 16(3):R58. doi: 10.1186/bcr3669. PMID: 24894818
  17. van, Lier, MG, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am. J. Gastroenterol. 2010; 105(6):1258-64; author reply 1265. PMID: 20051941
  18. Win, AK, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int. J. Cancer. 2011; 129(9):2256-62. doi: 10.1002/ijc.25870. PMID: 21171015
  19. Cybulski, C, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J. Clin. Oncol. 2011; 29(28):3747-52. doi: 10.1200/JCO.2010.34.0778. PMID: 21876083
  20. Marvin, ML, et al. AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome. Am. J. Med. Genet. A. 2011; 155A(4):898-902. doi: 10.1002/ajmg.a.33927. PMID: 21416598
  21. Rafnar, T, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat. Genet. 2011; 43(11):1104-7. PMID: 21964575
  22. Witkowski, L, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat. Genet. 2014; 46(5):438-43. doi: 10.1038/ng.2931. PMID: 24658002
  23. Thompson, D, et al. Cancer Incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 2002; 94(18):1358-65. doi: 10.1093/jnci/94.18.1358. PMID: 12237281
  24. Jaeger, E, et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat. Genet. 2012; 44(6):699-703. doi: 10.1038/ng.2263. PMID: 22561515
  25. Pharoah, PD, et al. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001; 121(6):1348-53. doi: 10.1053/gast.2001.29611. PMID: 11729114
  26. Loveday, C, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat. Genet. 2011; 43(9):879-82. PMID: 21822267
  27. Rennert, G, et al. MutYH mutation carriers have increased breast cancer risk. Cancer. 2012; 118(8):1989-93. doi: 10.1002/cncr.26506. PMID: 21952991
  28. Seal, S, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 2006; 38(11):1239-41. PMID: 17033622
  29. Vogt, S, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009; 137(6):1976-85.e1-10. doi: 10.1053/j.gastro.2009.08.052. PMID: 19732775
  30. Thompson, D, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J. Natl. Cancer Inst. 2005; 97(11):813-22. doi: 10.1093/jnci/dji141. PMID: 15928302
  31. Kaurah, P, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007; 297(21):2360-72. doi: 10.1001/jama.297.21.2360. PMID: 17545690
  32. Ni, Y, et al. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum. Mol. Genet. 2012; 21(2):300-10. doi: 10.1093/hmg/ddr459. PMID: 21979946
  33. Hansford, S, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015; 1(1):23-32. doi: 10.1001/jamaoncol.2014.168. PMID: 26182300
  34. Ratajska, M, et al. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res. Treat. 2012; 131(1):89-97. doi: 10.1007/s10549-011-1403-8. PMID: 21344236
  35. Lammi, L, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am. J. Hum. Genet. 2004; 74(5):1043-50. doi: 10.1086/386293. PMID: 15042511
  36. Schneider, K, et al. Li-Fraumeni Syndrome. 1999 Jan 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle. PMID: 20301488
  37. Aarnio, M. Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012; 2012:350309. doi: 10.1155/2012/350309. PMID: 22619739
  38. Janeway, KA, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc. Natl. Acad. Sci. U.S.A. 2011; 108(1):314-8. doi: 10.1073/pnas.1009199108. PMID: 21173220
  39. Ford, D, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994; 343(8899):692-5. doi: 10.1136/jmg.31.6.504-d. PMID: 7907678
  40. Thompson, ER, et al. Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS ONE. 2013; 8(1):e54772. PMID: 23372765
  41. Han, FF, et al. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol. 2013; 32(6):329-35. doi: 10.1089/dna.2013.1970. PMID: 23713947
  42. Castéra, L, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur. J. Hum. Genet. 2014; 22(11):1305-13. doi: 10.1038/ejhg.2014.16. PMID: 24549055
  43. Slade, I, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J. Med. Genet. 2011; 48(4):273-8. doi: 10.1136/jmg.2010.083790. PMID: 21266384
  44. Ford, D, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 1998; 62(3):676-89. doi: 10.1086/301749. PMID: 9497246
  45. Wong, P, et al. Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology. 2006; 130(1):73-9. doi: 10.1053/j.gastro.2005.10.014. PMID: 16401470
  46. Richards, FM, et al. Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum. Mol. Genet. 1999; 8(4):607-10. doi: 10.1093/hmg/8.4.607. PMID: 10072428
  47. Falchetti, A, et al. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet. Med. 2009; 11(12):825-35. doi: 10.1097/GIM.0b013e3181be5c97. PMID: 19904212
  48. Pasini, B, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur. J. Hum. Genet. 2008; 16(1):79-88. doi: 10.1038/sj.ejhg.5201904. PMID: 17667967
  49. Bonadona, V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011; 305(22):2304-10. doi: 10.1001/jama.2011.743. PMID: 21642682
  50. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  51. Pantaleo, MA, et al. Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST. Eur. J. Hum. Genet. 2014; 22(1):32-9. doi: 10.1038/ejhg.2013.80. PMID: 23612575
  52. Ruijs, MW, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J. Med. Genet. 2010; 47(6):421-8. PMID: 20522432
  53. Leoz, ML, et al. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. Appl Clin Genet. 2015; 8:95-107. doi: 10.2147/TACG.S51484. PMID: 25931827
  54. Wu, Y, et al. DICER1 mutations in a patient with an ovarian Sertoli-Leydig tumor, well-differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter. Eur J Med Genet. 2014; 57(11-12):621-5. doi: 10.1016/j.ejmg.2014.09.008. PMID: 25451712
  55. Thompson, D, et al. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol. Biomarkers Prev. 2006; 15(12):2542-5. PMID: 17164383
  56. Zhang, B, et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011; 12(5):477-88. PMID: 21514219
  57. Postow, MA, Robson, ME. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin Sarcoma Res. 2012; 2(1):16. doi: 10.1186/2045-3329-2-16. PMID: 23036227
  58. Loveday, C, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat. Genet. 2012; 44(5):475-6; author reply 476. PMID: 22538716
  59. Vasen, HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int. J. Cancer. 2000; 87(6):809-11. doi: 10.1016/s0016-5085(00)84701-0. PMID: 10956390
  60. Bianchi, LK, et al. Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(2):180-5. doi: 10.1016/j.cgh.2007.11.018. PMID: 18237868
  61. Bougeard, G, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J. Clin. Oncol. 2015; 33(21):2345-52. doi: 10.1200/JCO.2014.59.5728. PMID: 26014290
  62. Ni, Y, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. 2008; 83(2):261-8. PMID: 18678321
  63. Brosens, LA, et al. Risk of colorectal cancer in juvenile polyposis. Gut. 2007; 56(7):965-7. doi: 10.1136/gut.2006.116913. PMID: 17303595
  64. Dowty, JG, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum. Mutat. 2013; 34(3):490-7. doi: 10.1002/humu.22262. PMID: 23255516
  65. Stadler, ZK, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer. 2012; 118(2):493-9. doi: 10.1002/cncr.26191. PMID: 21598239
  66. Moran, A, et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam. Cancer. 2012; 11(2):235-42. PMID: 22187320
  67. Steffen, J, et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int. J. Cancer. 2006; 119(2):472-5. PMID: 16770759
  68. Chompret, A, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. 2004; 126(1):318-21. doi: 10.1053/j.gastro.2003.10.079. PMID: 14699510
  69. Mazzoni, SM, et al. An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function. Neoplasia. 2015; 17(5):463-72. doi: 10.1016/j.neo.2015.04.006. PMID: 26025668
  70. Syngal, S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 2015; 110(2):223-62; quiz 263. doi: 10.1038/ajg.2014.435. PMID: 25645574
  71. Engel, C, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J. Clin. Oncol. 2012; 30(35):4409-15. doi: 10.1200/JCO.2012.43.2278. PMID: 23091106
  72. Toss, A, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. 2015; 2015:341723. doi: 10.1155/2015/341723. PMID: 26075229
  73. Slater, EP, et al. PALB2 mutations in European familial pancreatic cancer families. Clin. Genet. 2010; 78(5):490-4. doi: 10.1111/j.1399-0004.2010.01425.x. PMID: 20412113
  74. Brand, R, et al. MUTYH-Associated Polyposis. 2012 Oct 04. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK107219/ PMID: 23035301
  75. Thakker, RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell. Endocrinol. 2014; 386(1-2):2-15. doi: 10.1016/j.mce.2013.08.002. PMID: 23933118
  76. Kempers, MJ, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 2011; 12(1):49-55. doi: 10.1016/S1470-2045(10)70265-5. PMID: 21145788
  77. Minion, LE, et al. Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2. Gynecol. Oncol. 2015; 137(1):86-92. doi: 10.1016/j.ygyno.2015.01.537. PMID: 25622547
  78. de, Raedt, T, et al. Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology. 2006; 131(6):1907-12. doi: 10.1053/j.gastro.2006.07.002. PMID: 17087943
  79. Lubbe, SJ, et al. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J. Clin. Oncol. 2009; 27(24):3975-80. doi: 10.1200/JCO.2008.21.6853. PMID: 19620482
  80. Barrow, E, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin. Genet. 2009; 75(2):141-9. doi: 10.1111/j.1399-0004.2008.01125.x. PMID: 19215248
  81. Coulet, F, et al. Germline RAD51C mutations in ovarian cancer susceptibility. Clin. Genet. 2013; 83(4):332-6. doi: 10.1111/j.1399-0004.2012.01917.x. PMID: 22725699
  82. Teodorczyk, U, et al. The risk of gastric cancer in carriers of CHEK2 mutations. Fam. Cancer. 2013; 12(3):473-8. doi: 10.1007/s10689-012-9599-2. PMID: 23296741
  83. Debniak, T, et al. A common variant of CDKN2A (p16) predisposes to breast cancer. J. Med. Genet. 2005; 42(10):763-5. doi: 10.1136/jmg.2005.031476. PMID: 15879498
  84. Antoniou, A, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 2003; 72(5):1117-30. doi: 10.1086/375033. PMID: 12677558
  85. Spier, I, et al. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int. J. Cancer. 2015; 137(2):320-31. PMID: 25529843
  86. Foulkes, WD, et al. No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J. Pathol. 2014; 233(3):209-14. doi: 10.1002/path.4362. PMID: 24752781
  87. Davis, H, et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 2015; 21(1):62-70. doi: 10.1038/nm.3750. PMID: 25419707
  88. Chompret, A, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer. 2000; 82(12):1932-7. doi: 10.1054/bjoc.2000.1167. PMID: 10864200
  89. Ricci, R, et al. PDGFRA-mutant syndrome. Mod. Pathol. 2015; 28(7):954-64. doi: 10.1038/modpathol.2015.56. PMID: 25975287
  90. Fitzgerald, RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J. Med. Genet. 2010; 47(7):436-44. doi: 10.1136/jmg.2009.074237. PMID: 20591882
  91. Mohelnikova-Duchonova, B, et al. CHEK2 gene alterations in the forkhead-associated domain, 1100delC and del5395 do not modify the risk of sporadic pancreatic cancer. Cancer Epidemiol. 2010; 34(5):656-8. doi: 10.1016/j.canep.2010.06.008. PMID: 20643596
  92. Giardiello, FM, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993; 34(10):1394-6. doi: 10.1136/gut.34.10.1394. PMID: 8244108
  93. Roberts, NJ, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012; 2(1):41-6. doi: 10.1158/2159-8290.CD-11-0194. PMID: 22585167
  94. Olivier, M, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003; 63(20):6643-50. PMID: 14583457
  95. Jones, S, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009; 324(5924):217. doi: 10.1126/science.1171202. PMID: 19264984
  96. Half, E, et al. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009; 4:22. doi: 10.1186/1750-1172-4-22. PMID: 19822006
  97. Le, Calvez-Kelm, F, et al. RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study. PLoS ONE. 2012; 7(12):e52374. PMID: 23300655
  98. Kastrinos, F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009; 302(16):1790-5. doi: 10.1001/jama.2009.1529. PMID: 19861671
  99. Phelan, CM, et al. Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study. Br. J. Cancer. 2014; 110(2):530-4. doi: 10.1038/bjc.2013.741. PMID: 24292448
  100. Weischer, M, et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J. Clin. Oncol. 2008; 26(4):542-8. doi: 10.1200/JCO.2007.12.5922. PMID: 18172190
  101. Xiang, HP, et al. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur. J. Cancer. 2011; 47(17):2546-51. PMID: 21807500
  102. van, Asperen, CJ, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J. Med. Genet. 2005; 42(9):711-9. PMID: 16141007
  103. Groen, EJ, et al. Extra-intestinal manifestations of familial adenomatous polyposis. Ann. Surg. Oncol. 2008; 15(9):2439-50. doi: 10.1245/s10434-008-9981-3. PMID: 18612695
  104. Borg, A, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J. Natl. Cancer Inst. 2000; 92(15):1260-6. doi: 10.1093/jnci/92.15.1260. PMID: 10922411
  105. Baglietto, L, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J. Natl. Cancer Inst. 2010; 102(3):193-201. doi: 10.1093/jnci/djp473. PMID: 20028993
  106. Poumpouridou, N, Kroupis, C. Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges. Clin. Chem. Lab. Med. 2012; 50(3):423-34. doi: 10.1515/cclm-2011-0840. PMID: 22505525
  107. Ebi, H, et al. Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of cancer. Cancer Res. 2007; 67(23):11158-65. doi: 10.1158/0008-5472.CAN-07-1749. PMID: 18056440
  108. Iqbal, J, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer. 2012; 107(12):2005-9. doi: 10.1038/bjc.2012.483. PMID: 23099806
  109. Ow, GS, et al. Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. Cell Cycle. 2014; 13(14):2262-80. doi: 10.4161/cc.29271. PMID: 24879340
  110. Barnetson, RA, et al. Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin. Genet. 2007; 72(6):551-5. doi: 10.1111/j.1399-0004.2007.00900.x. PMID: 17956577
  111. Giardiello, FM, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am. J. Gastroenterol. 2014; 109(8):1159-79. doi: 10.1038/ajg.2014.186. PMID: 25070057
  112. Pelttari, LM, et al. RAD51C is a susceptibility gene for ovarian cancer. Hum. Mol. Genet. 2011; 20(16):3278-88. PMID: 21616938
  113. Cassol, C, Mete, O. Endocrine manifestations of von Hippel-Lindau disease. Arch. Pathol. Lab. Med. 2015; 139(2):263-8. doi: 10.5858/arpa.2013-0520-RS. PMID: 25611110
  114. Hendriks, YM, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 2004; 127(1):17-25. PMID: 15236168
  115. Pollock, J, Welsh, JS. Clinical cancer genetics: Part I: Gastrointestinal. Am. J. Clin. Oncol. 2011; 34(3):332-6. doi: 10.1097/COC.0b013e3181dea432. PMID: 20859198
  116. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  117. Italiano, A, et al. SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors. BMC Cancer. 2012; 12:408. doi: 10.1186/1471-2407-12-408. PMID: 22974104
  118. Masciari, S, et al. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet. Med. 2011; 13(7):651-7. doi: 10.1097/GIM.0b013e31821628b6. PMID: 21552135
  119. Ramus, SJ, et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J. Natl. Cancer Inst. 2015; 107(11):None. PMID: 26315354
  120. Mahdi, H, et al. Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study. Cancer. 2015; 121(5):688-96. PMID: 25376524
  121. McWilliams, RR, et al. Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur. J. Hum. Genet. 2011; 19(4):472-8. PMID: 21150883
  122. Karlsson, R, et al. A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk. Eur. Urol. 2014; 65(1):169-76. PMID: 22841674
  123. Kote-Jarai, Z, et al. Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes. Ann. Oncol. 2015; 26(4):756-61. PMID: 25595936
  124. Li, D, et al. The role of BRCA1 and BRCA2 in prostate cancer. Front Biosci (Landmark Ed). 2013; 18:1445-59. PMID: 23747895
  125. Liede, A, et al. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J. Clin. Oncol. 2004; 22(4):735-42. PMID: 14966099
  126. MacInnis, RJ, et al. Population-based estimate of prostate cancer risk for carriers of the HOXB13 missense mutation G84E. PLoS ONE. 2013; 8(2):e54727. PMID: 23457453
  127. Raymond, VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J. Clin. Oncol. 2013; 31(14):1713-8. PMID: 23530095
  128. Ryan, S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 2014; 23(3):437-49. PMID: 24425144
  129. Stott-Miller, M, et al. HOXB13 mutations in a population-based, case-control study of prostate cancer. Prostate. 2013; 73(6):634-41. PMID: 23129385
  130. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed January 2018.
  131. National Library of Medicine Genetics Home Reference. Prostate cancer. http://ghr.nlm.nih.gov/condition/prostate-cancer. Accessed January 2018.
  132. U.S. Department of Health and Human Services. What is Your Prostate? http://archive.ahrq.gov/patients-consumers/prevention/understanding/bodysys/edbody13.html, Accessed January 2018.
  133. Pritchard, CC. et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. NEJM, 2016 PMID: 27433846
  134. Giri, VN, et al. Inherited Mutations in Men Undergoing Multigene Panel Testing for Prostate Cancer: Emerging Implications for Personalized Prostate Cancer Genetic Evaluation. JCO Precision Oncology, 2017
  135. Aarnio, M, et al. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int. J. Cancer. 1995; 64(6):430-3. PMID: 8550246
  136. Vasen, HF, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013; 62(6):812-23. PMID: 23408351
  137. Ericson, KM, et al. Low frequency of defective mismatch repair in a population-based series of upper urothelial carcinoma. BMC Cancer. 2005; 5:23. PMID: 15740628
  138. Aarnio, M, et al. Uroepithelial and kidney carcinoma in Lynch syndrome. Fam. Cancer. 2012; 11(3):395-401. PMID: 22476430
  139. Skeldon, SC, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur. Urol. 2013; 63(2):379-85. PMID: 22883484
  140. Obermair, A, et al. Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int. J. Cancer. 2010; 127(11):2678-84. PMID: 20533284
  141. Rivera, B, et al. A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia. Eur. J. Hum. Genet. 2014; 22(3):423-6. doi: 10.1038/ejhg.2013.146. PMID: 23838596
  142. Lejeune, S, et al. Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis. Hum. Mutat. 2006; 27(10):1064. PMID: 16941501
  143. Wong, S, et al. Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia. Arch. Oral Biol. 2014; 59(3):349-53. PMID: 24581859
  144. Pan, KF, et al. Mutations in components of the Wnt signaling pathway in gastric cancer. World J. Gastroenterol. 2008; 14(10):1570-4. doi: 10.3748/wjg.14.1570. PMID: 18330950
  145. Bergendal, B, et al. Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes. Am. J. Med. Genet. A. 2011; 155A(7):1616-22. PMID: 21626677
  146. Jasperson, KW, Burt, RW. APC-Associated Polyposis Conditions. 1998 Dec 18. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301519
  147. Li, J, et al. Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. Am. J. Hum. Genet. 2016; 98(5):830-42. PMID: 27087319
  148. Bisgaard, ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat. 1994; 3(2):121-5. PMID: 8199592
  149. Spirio, L, et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. 1993; 75(5):951-7. doi: 10.1016/0092-8674(93)90538-2. PMID: 8252630
  150. Burt, RW, et al. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology. 2004; 127(2):444-51. PMID: 15300576
  151. Sieber, OM, et al. Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut. 2006; 55(10):1440-8. PMID: 16461775
  152. van, der, Luijt, RB, et al. APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. Hum. Genet. 1995; 96(6):705-10. PMID: 8522331
  153. Friedl, W, et al. Attenuated familial adenomatous polyposis due to a mutation in the 3' part of the APC gene. A clue for understanding the function of the APC protein. Hum. Genet. 1996; 97(5):579-84. PMID: 8655134
  154. Laken, SJ, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat. Genet. 1997; 17(1):79-83. PMID: 9288102
  155. Liang, J, et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am. J. Epidemiol. 2013; 177(11):1169-79. PMID: 23576677
  156. Robson, ME, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J. Clin. Oncol. 2010; 28(5):893-901. PMID: 20065170
  157. Boursi, B, et al. The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews. Eur. J. Cancer. 2013; 49(17):3680-5. PMID: 23896379
  158. Repak, R, et al. The first European family with gastric adenocarcinoma and proximal polyposis of the stomach: case report and review of the literature. Gastrointest. Endosc. 2016; 84(4):718-25. PMID: 27343414
  159. Worthley, DL, et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut. 2012; 61(5):774-9. PMID: 21813476
  160. Liu, C, et al. The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pac. J. Cancer Prev. 2012; 13(4):1355-60. PMID: 22799331
  161. Gronwald, J, et al. Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband. Br. J. Cancer. 2009; 100(9):1508-12. PMID: 19401704
  162. Cybulski, C, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet. 2004; 75(6):1131-5. PMID: 15492928
  163. Wasielewski, M, et al. CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res. Treat. 2009; 116(2):397-400. PMID: 18759107
  164. Hale, V, et al. CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer. Prostate Cancer. 2014; 2014:294575. PMID: 25431674
  165. Adam, R, et al. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am. J. Hum. Genet. 2016; 99(2):337-51. PMID: 27476653
  166. Cleary, SP, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009; 136(4):1251-60. PMID: 19245865
  167. Jones, N, et al. Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009; 137(2):489-94, 494.e1; quiz 725-6. PMID: 19394335
  168. Win, AK, et al. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology. 2014; 146(5):1208-11.e1-5. PMID: 24444654
  169. Jenkins, MA, et al. Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol. Biomarkers Prev. 2006; 15(2):312-4. PMID: 16492921
  170. Weren, RD, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat. Genet. 2015; :None. PMID: 25938944
  171. Rivera, B, et al. Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors. N. Engl. J. Med. 2015; 373(20):1985-6. PMID: 26559593
  172. Kuiper, RP, Hoogerbrugge, N. NTHL1 defines novel cancer syndrome. Oncotarget. 2015; 6(33):34069-70. PMID: 26431160
  173. Belhadj, S, et al. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis. Clin. Gastroenterol. Hepatol. 2017; 15(3):461-462. PMID: 27720914
  174. Broderick, P, et al. Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC Cancer. 2006; 6:243. PMID: 17029639
  175. Broderick, P, et al. Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review. Gastroenterology. 2017; 152(1):75-77.e4. PMID: 27713038
  176. Briggs, S, Tomlinson, I. Germline and somatic polymerase ε and ō mutations define a new class of hypermutated colorectal and endometrial cancers. J. Pathol. 2013; 230(2):148-53. doi: 10.1002/path.4185. PMID: 23447401
  177. Elsayed, FA, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur. J. Hum. Genet. 2014; :None. doi: 10.1038/ejhg.2014.242. PMID: 25370038
  178. Stenzinger, A, et al. Mutations in POLE and survival of colorectal cancer patients–link to disease stage and treatment. Cancer Med. 2014; 3(6):1527-38. doi: 10.1002/cam4.305. PMID: 25124163
  179. Weedon, MN, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat. Genet. 2013; 45(8):947-50. doi: 10.1038/ng.2670. PMID: 23770608
  180. Esteban-Jurado, C, et al. New genes emerging for colorectal cancer predisposition. World J. Gastroenterol. 2014; 20(8):1961-71. doi: 10.3748/wjg.v20.i8.1961. PMID: 24587672
  181. Chubb, D, et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J. Clin. Oncol. 2015; 33(5):426-32. doi: 10.1200/JCO.2014.56.5689. PMID: 25559809
  182. Church, JM. Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Dis. Colon Rectum. 2014; 57(3):396-7. doi: 10.1097/DCR.0000000000000084. PMID: 24509466
  183. Smith, CG, et al. Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer. Hum. Mutat. 2013; 34(7):1026-34. doi: 10.1002/humu.22333. PMID: 23585368
  184. Valle, L, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum. Mol. Genet. 2014; 23(13):3506-12. doi: 10.1093/hmg/ddu058. PMID: 24501277
  185. Rohlin, A, et al. A mutation in POLE predisposing to a multi-tumour phenotype. Int. J. Oncol. 2014; 45(1):77-81. doi: 10.3892/ijo.2014.2410. PMID: 24788313
  186. Pachlopnik, Schmid, J, et al. Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome"). J. Exp. Med. 2012; 209(13):2323-30. PMID: 23230001
  187. Thiffault, I, et al. A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes. BMC Med. Genet. 2015; 16:31. PMID: 25948378
  188. Biesecker, LG, et al. PTEN mutations and proteus syndrome. Lancet. 2001; 358(9298):2079-80. PMID: 11755638
  189. Caux, F, et al. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Eur. J. Hum. Genet. 2007; 15(7):767-73. PMID: 17392703
  190. Nathan, N, et al. Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway. Dermatol Clin. 2017; 35(1):51-60. PMID: 27890237
  191. Mester, J, Eng, C. Cowden syndrome: recognizing and managing a not-so-rare hereditary cancer syndrome. J Surg Oncol. 2015; 111(1):125-30. PMID: 25132236
  192. Leslie, NR, Longy, M. Inherited PTEN mutations and the prediction of phenotype. Semin. Cell Dev. Biol. 2016; 52:30-8. PMID: 26827793
  193. Eng, C. PTEN Hamartoma Tumor Syndrome (PHTS). 2001 Nov 29. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1488/ PMID: 20301661
  194. Marsh, DJ, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum. Mol. Genet. 1999; 8(8):1461-72. PMID: 10400993
  195. Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 2003; 22(3):183-98. PMID: 12938083
  196. Riegert-Johnson, DL, et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010; 8(1):6. PMID: 20565722
  197. Pilarski, R, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J. Natl. Cancer Inst. 2013; 105(21):1607-16. PMID: 24136893
  198. Mester, J, Charis, E. PTEN hamartoma tumor syndrome. Handb Clin Neurol. 2015; 132:129-37. PMID: 26564076
  199. Varga, EA, et al. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet. Med. 2009; 11(2):111-7. PMID: 19265751
  200. Frazier, TW, et al. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Mol. Psychiatry. 2015; 20(9):1132-8. PMID: 25288137
  201. Hearle, N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin. Cancer Res. 2006; 12(10):3209-15. PMID: 16707622
  202. McGarrity, TJ, et al. Peutz-Jeghers Syndrome. 2001 Feb 23. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1266/ PMID: 20301443
  203. Gonzalez, KD, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J. Med. Genet. 2009; 46(10):689-93. PMID: 19556618
  204. Olsen, JH, et al. Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br. J. Cancer. 2005; 93(2):260-5. PMID: 15942625
  205. Hu, C, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. Cancer Epidemiol. Biomarkers Prev. 2015; :None. PMID: 26483394
  206. van, Os, NJ, et al. Health risks for ataxia-telangiectasia mutated heterozygotes: A systematic review, Meta-analysis and evidence-based guideline. Clin. Genet. 2015; :None. PMID: 26662178
  207. Na, R, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur. Urol. 2017; 71(5):740-747. PMID: 27989354
  208. Chenevix-Trench, G, et al. Dominant negative ATM mutations in breast cancer families. J. Natl. Cancer Inst. 2002; 94(3):205-15. PMID: 11830610
  209. Renwick, A, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 2006; 38(8):873-5. doi: 10.1038/ng1837. PMID: 16832357
  210. Bernstein, JL, et al. Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry. Hum. Mutat. 2006; 27(11):1122-8. PMID: 16958054
  211. Goldgar, DE, et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011; 13(4):R73. PMID: 21787400
  212. Southey, MC, et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J. Med. Genet. 2016; :None. PMID: 27595995
  213. Helgason, H, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat. Genet. 2015; 47(8):906-10. PMID: 26098866
  214. Cheng, HH, et al. A Pilot Study of Clinical Targeted Next Generation Sequencing for Prostate Cancer: Consequences for Treatment and Genetic Counseling. Prostate. 2016; 76(14):1303-1311. PMID: 27324988
  215. Karppinen, SM, et al. Nordic collaborative study of the BARD1 Cys557Ser allele in 3956 patients with cancer: enrichment in familial BRCA1/BRCA2 mutation-negative breast cancer but not in other malignancies. J. Med. Genet. 2006; 43(11):856-62. doi: 10.1136/jmg.2006.041731. PMID: 16825437
  216. Hopper, JL, et al. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol. Biomarkers Prev. 1999; 8(9):741-7. PMID: 10498392
  217. King, MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003; 302(5645):643-6. doi: 10.1126/science.1088759. PMID: 14576434
  218. Struewing, JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N. Engl. J. Med. 1997; 336(20):1401-8. PMID: 9145676
  219. Metcalfe, K, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J. Clin. Oncol. 2004; 22(12):2328-35. doi: 10.1200/JCO.2004.04.033. PMID: 15197194
  220. Evans, DG, et al. Risk of breast cancer in male BRCA2 carriers. J. Med. Genet. 2010; 47(10):710-1. doi: 10.1136/jmg.2009.075176. PMID: 20587410
  221. Tai, YC, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J. Natl. Cancer Inst. 2007; 99(23):1811-4. doi: 10.1093/jnci/djm203. PMID: 18042939
  222. Easton, DF, et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J. Med. Genet. 2016; :None. PMID: 26921362
  223. Kaurah, P, Huntsman, DG. Hereditary Diffuse Gastric Cancer. 2002 Nov 04. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1139/ PMID: 20301318
  224. Goldstein, AM, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J. Med. Genet. 2007; 44(2):99-106. doi: 10.1136/jmg.2006.043802. PMID: 16905682
  225. Goldstein, AM, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006; 66(20):9818-28. doi: 10.1158/0008-5472.CAN-06-0494. PMID: 17047042
  226. Harinck, F, et al. Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas. J. Med. Genet. 2012; 49(6):362-5. PMID: 22636603
  227. Bishop, DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J. Natl. Cancer Inst. 2002; 94(12):894-903. doi: 10.1093/jnci/94.12.894. PMID: 12072543
  228. Begg, CB, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J. Natl. Cancer Inst. 2005; 97(20):1507-15. doi: 10.1093/jnci/dji312. PMID: 16234564
  229. Helgadottir, H, et al. High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families. J. Med. Genet. 2014; 51(8):545-52. PMID: 24935963
  230. Majewski, IJ, et al. An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J. Pathol. 2013; 229(4):621-9. doi: 10.1002/path.4152. PMID: 23208944
  231. Hill, DA, et al. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009; 325(5943):965. PMID: 19556464
  232. Rio, Frio, T, et al. DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA. 2011; 305(1):68-77. doi: 10.1001/jama.2010.1910. PMID: 21205968
  233. Ewing, CM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N. Engl. J. Med. 2012; 366(2):141-9. PMID: 22236224
  234. Xu, J, et al. HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum. Genet. 2013; 132(1):5-14. PMID: 23064873
  235. Cai, Q, et al. Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget. 2015; 6(39):42312-21. PMID: 26517352
  236. Beebe-Dimmer, JL, et al. The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies. Cancer Epidemiol. Biomarkers Prev. 2015; 24(9):1366-72. PMID: 26108461
  237. Hoffmann, TJ, et al. Imputation of the rare HOXB13 G84E mutation and cancer risk in a large population-based cohort. PLoS Genet. 2015; 11(1):e1004930. PMID: 25629170
  238. Huang, H, Cai, B. G84E mutation in HOXB13 is firmly associated with prostate cancer risk: a meta-analysis. Tumour Biol. 2014; 35(2):1177-82. PMID: 24026887
  239. Thakker, RV. Multiple endocrine neoplasia type 1. Indian J Endocrinol Metab. 2012; 16(Suppl 2):S272-4. PMID: 23565397
  240. Brandi, ML, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J. Clin. Endocrinol. Metab. 2001; 86(12):5658-71. doi: 10.1210/jcem.86.12.8070. PMID: 11739416
  241. Thakker, RV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 2012; 97(9):2990-3011. doi: 10.1210/jc.2012-1230. PMID: 22723327
  242. Norton, JA, et al. Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surg. Oncol. Clin. N. Am. 2015; 24(4):795-832. PMID: 26363542
  243. Miedlich, S, et al. Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant?. Eur. J. Endocrinol. 2001; 145(2):155-60. PMID: 11454510
  244. Villablanca, A, et al. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur. J. Endocrinol. 2002; 147(3):313-22. PMID: 12213668
  245. Pannett, AA, et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2003; 58(5):639-46. doi: 10.1046/j.1365-2265.2003.01765.x. PMID: 12699448
  246. Bachet, JB, et al. Diagnosis, prognosis and treatment of patients with gastrointestinal stromal tumour (GIST) and germline mutation of KIT exon 13. Eur. J. Cancer. 2013; 49(11):2531-41. doi: 10.1016/j.ejca.2013.04.005. PMID: 23648119
  247. Watson, GA, et al. Get the GIST? An overview of gastrointestinal stromal tumours. Ir J Med Sci. 2016; :None. PMID: 26833487
  248. Hirota, S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. PMID: 9438854
  249. Carballo, M, et al. Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am. J. Med. Genet. A. 2005; 132A(4):361-4. doi: 10.1002/ajmg.a.30388. PMID: 15742474
  250. Gao, P, et al. Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies. Mutagenesis. 2013; 28(6):683-97. PMID: 24113799
  251. Resnick, IB, et al. 657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls. Am. J. Med. Genet. A. 2003; 120A(2):174-9. doi: 10.1002/ajmg.a.20188. PMID: 12833396
  252. di, Masi, A, Antoccia, A. NBS1 Heterozygosity and Cancer Risk. Curr. Genomics. 2008; 9(4):275-81. doi: 10.2174/138920208784533610. PMID: 19452044
  253. Cybulski, C, et al. NBS1 is a prostate cancer susceptibility gene. Cancer Res. 2004; 64(4):1215-9. doi: 10.1158/0008-5472.can-03-2502. PMID: 14973119
  254. Dzikiewicz-Krawczyk, A. The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer. Mutat. Res. 2008; 659(3):262-73. PMID: 18606567
  255. Ciara, E, et al. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 2010; 119(3):325-34. PMID: 19908051
  256. Rahman, N, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 2007; 39(2):165-7. doi: 10.1038/ng1959. PMID: 17200668
  257. Erkko, H, et al. Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin. Cancer Res. 2008; 14(14):4667-71. doi: 10.1158/1078-0432.CCR-08-0210. PMID: 18628482
  258. Erkko, H, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007; 446(7133):316-9. PMID: 17287723
  259. Pakkanen, S, et al. PALB2 variants in hereditary and unselected Finnish prostate cancer cases. J Negat Results Biomed. 2009; 8:12. PMID: 20003494
  260. Tischkowitz, M, et al. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer. Prostate. 2008; 68(6):675-8. PMID: 18288683
  261. Casadei S, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011 Mar 15;71(6):2222-9. PMID: 21285249
  262. Heikkinen, K, et al. Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. J. Med. Genet. 2003; 40(12):e131. doi: 10.1136/jmg.40.12.e131. PMID: 14684699
  263. Osorio, A, et al. Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum. Mol. Genet. 2012; 21(13):2889-98. doi: 10.1093/hmg/dds115. PMID: 22451500
  264. Vaz, F, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat. Genet. 2010; 42(5):406-9. PMID: 20400963
  265. Song, H, et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J. Clin. Oncol. 2015; :None. PMID: 26261251
  266. Pelttari, LM, et al. A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer. J. Med. Genet. 2012; 49(7):429-32. PMID: 22652533
  267. Pantaleo, MA, et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J. Natl. Cancer Inst. 2011; 103(12):983-7. PMID: 21505157
  268. Dwight, T, et al. Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am. J. Surg. Pathol. 2013; 37(2):226-33. doi: 10.1097/PAS.0b013e3182671155. PMID: 23060355
  269. Korpershoek, E, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J. Clin. Endocrinol. Metab. 2011; 96(9):E1472-6. PMID: 21752896
  270. Burnichon, N, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 2010; 19(15):3011-20. doi: 10.1093/hmg/ddq206. PMID: 20484225
  271. Buffet, A, et al. A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. Horm. Metab. Res. 2012; 44(5):359-66. PMID: 22517557
  272. Jiang, Q, et al. A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma. Int J Clin Exp Pathol. 2015; 8(10):12188-97. PMID: 26722403
  273. Williamson, SR, et al. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod. Pathol. 2015; 28(1):80-94. PMID: 25034258
  274. Ricketts, C, et al. Germline SDHB mutations and familial renal cell carcinoma. J. Natl. Cancer Inst. 2008; 100(17):1260-2. doi: 10.1093/jnci/djn254. PMID: 18728283
  275. Schiavi, F, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005; 294(16):2057-63. PMID: 16249420
  276. Peczkowska, M, et al. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab. 2008; 4(2):111-5. PMID: 18212813
  277. Ricketts, CJ, et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J. Urol. 2012; 188(6):2063-71. PMID: 23083876
  278. Miettinen, M, Lasota, J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int. J. Biochem. Cell Biol. 2014; 53:514-9. doi: 10.1016/j.biocel.2014.05.033. PMID: 24886695
  279. Neumann, HP, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004; 292(8):943-51. PMID: 15328326
  280. Benn, DE, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 2006; 91(3):827-36. PMID: 16317055
  281. Ramos, P, et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat. Genet. 2014; 46(5):427-9. doi: 10.1038/ng.2928. PMID: 24658001
  282. Jelinic, P, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat. Genet. 2014; 46(5):424-6. PMID: 24658004
  283. Sredni, ST, Tomita, T. Rhabdoid tumor predisposition syndrome. Pediatr. Dev. Pathol. 2015; 18(1):49-58. doi: 10.2350/14-07-1531-MISC.1. PMID: 25494491
  284. Witkowski, L, et al. Familial rhabdoid tumour 'avant la lettre'--from pathology review to exome sequencing and back again. J. Pathol. 2013; 231(1):35-43. PMID: 23775540
  285. Northrup, H, et al. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol. 2013; 49(4):243-54. doi: 10.1016/j.pediatrneurol.2013.08.001. PMID: 24053982
  286. Joinson, C, et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med. 2003; 33(2):335-44. PMID: 12622312
  287. Goh, S, et al. Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology. 2005; 65(2):235-8. PMID: 16043792
  288. Shepherd, CW, et al. Causes of death in patients with tuberous sclerosis. Mayo Clin. Proc. 1991; 66(8):792-6. PMID: 1861550
  289. Borkowska, J, et al. Tuberous sclerosis complex: tumors and tumorigenesis. Int. J. Dermatol. 2011; 50(1):13-20. doi: 10.1111/j.1365-4632.2010.04727.x. PMID: 21182496
  290. Frantzen, C, et al. Von Hippel-Lindau Syndrome. 2000 May 17. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1463/ PMID: 20301636
  291. Neklason, DW, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(1):46-52. PMID: 18063416

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
APC* NM_000038.5
ATM NM_000051.3
AXIN2 NM_004655.3
BARD1 NM_000465.3
BMPR1A* NM_004329.2
BRCA1* NM_007294.3
BRCA2* NM_000059.3
BRIP1 NM_032043.2
CDH1 NM_004360.3
CDK4 NM_000075.3
CDKN2A* NM_000077.4; NM_058195.3
CHEK2 NM_007194.3
CTNNA1 NM_001903.3
DICER1 NM_177438.2
EPCAM* NM_002354.2
GREM1* NM_013372.6
HOXB13* NM_006361.5
KIT NM_000222.2
MEN1 NM_130799.2
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH3 NM_002439.4
MSH6 NM_000179.2
MUTYH NM_001128425.1
NBN NM_002485.4
NF1 NM_000267.3
NTHL1 NM_002528.6
PALB2 NM_024675.3
PDGFRA NM_006206.4
PMS2 NM_000535.5
POLD1 NM_002691.3
POLE NM_006231.3
PTEN* NM_000314.4
RAD50 NM_005732.3
RAD51C NM_058216.2
RAD51D NM_002878.3
SDHA* NM_004168.3
SDHB NM_003000.2
SDHC NM_003001.3
SDHD NM_003002.3
SMAD4 NM_005359.5
SMARCA4 NM_001128849.1
STK11 NM_000455.4
TP53* NM_000546.5
TSC1 NM_000368.4
TSC2 NM_000548.3
VHL NM_000551.3

APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.
BMPR1A: Deletion/duplication analysis covers the promoter region.
BRCA1: Sequence analysis includes +/- 20 base pairs of adjacent intronic sequence.
BRCA2: Sequence analysis includes +/- 20 base pairs of adjacent intronic sequence.
CDKN2A: Analysis supports interpretation of the p14 and p16 proteins.
EPCAM: Analysis is limited to deletion/duplication analysis.
GREM1: Analysis of this gene is limited to deletion/duplication analysis of the promoter region.
HOXB13: Analysis is limited to the NM_006361.5:c.251G>A, p.Gly84Glu variant.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).
PTEN: Deletion/duplication analysis covers the promoter region.
SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.
TP53: Deletion/duplication analysis covers the promoter region.

Clinical resources
Genes and associated cancers chart Hereditary cancer gene list Hereditary cancer risks and references chart Invitae brochure
Patient resources
Patient guide: Genetic testing for hereditary cancer Patient guide: Genetic testing simplified Patient guide: Hereditary breast cancer Patient guide: Hereditary colorectal cancer
Test information
Forms page Specimen requirements page

References

  1. Aarnio, M, et al. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int. J. Cancer. 1995; 64(6):430-3. PMID: 8550246
  2. Aarnio, M, et al. Uroepithelial and kidney carcinoma in Lynch syndrome. Fam. Cancer. 2012; 11(3):395-401. PMID: 22476430
  3. Aarnio, M. Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012; 2012:350309. doi: 10.1155/2012/350309. PMID: 22619739
  4. Adam, R, et al. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am. J. Hum. Genet. 2016; 99(2):337-51. PMID: 27476653
  5. Ahmed, M, Rahman, N. ATM and breast cancer susceptibility. Oncogene. 2006; 25(43):5906-11. doi: 10.1038/sj.onc.1209873. PMID: 16998505
  6. Antoniou, A, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 2003; 72(5):1117-30. doi: 10.1086/375033. PMID: 12677558
  7. Antoniou, AC, et al. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med. 2014; 371(6):497-506. doi: 10.1056/NEJMoa1400382. PMID: 25099575
  8. Bachet, JB, et al. Diagnosis, prognosis and treatment of patients with gastrointestinal stromal tumour (GIST) and germline mutation of KIT exon 13. Eur. J. Cancer. 2013; 49(11):2531-41. doi: 10.1016/j.ejca.2013.04.005. PMID: 23648119
  9. Baglietto, L, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J. Natl. Cancer Inst. 2010; 102(3):193-201. doi: 10.1093/jnci/djp473. PMID: 20028993
  10. Barnetson, RA, et al. Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin. Genet. 2007; 72(6):551-5. doi: 10.1111/j.1399-0004.2007.00900.x. PMID: 17956577
  11. Barrow, E, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin. Genet. 2009; 75(2):141-9. doi: 10.1111/j.1399-0004.2008.01125.x. PMID: 19215248
  12. Beebe-Dimmer, JL, et al. The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies. Cancer Epidemiol. Biomarkers Prev. 2015; 24(9):1366-72. PMID: 26108461
  13. Begg, CB, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J. Natl. Cancer Inst. 2005; 97(20):1507-15. doi: 10.1093/jnci/dji312. PMID: 16234564
  14. Belhadj, S, et al. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis. Clin. Gastroenterol. Hepatol. 2017; 15(3):461-462. PMID: 27720914
  15. Bellido, F, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.75. PMID: 26133394
  16. Benn, DE, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 2006; 91(3):827-36. PMID: 16317055
  17. Bergendal, B, et al. Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes. Am. J. Med. Genet. A. 2011; 155A(7):1616-22. PMID: 21626677
  18. Bernstein, JL, et al. Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry. Hum. Mutat. 2006; 27(11):1122-8. PMID: 16958054
  19. Bianchi, LK, et al. Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(2):180-5. doi: 10.1016/j.cgh.2007.11.018. PMID: 18237868
  20. Biesecker, LG, et al. PTEN mutations and proteus syndrome. Lancet. 2001; 358(9298):2079-80. PMID: 11755638
  21. Bisgaard, ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat. 1994; 3(2):121-5. PMID: 8199592
  22. Bishop, DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J. Natl. Cancer Inst. 2002; 94(12):894-903. doi: 10.1093/jnci/94.12.894. PMID: 12072543
  23. Bonadona, V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011; 305(22):2304-10. doi: 10.1001/jama.2011.743. PMID: 21642682
  24. Borg, A, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J. Natl. Cancer Inst. 2000; 92(15):1260-6. doi: 10.1093/jnci/92.15.1260. PMID: 10922411
  25. Borkowska, J, et al. Tuberous sclerosis complex: tumors and tumorigenesis. Int. J. Dermatol. 2011; 50(1):13-20. doi: 10.1111/j.1365-4632.2010.04727.x. PMID: 21182496
  26. Bougeard, G, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J. Clin. Oncol. 2015; 33(21):2345-52. doi: 10.1200/JCO.2014.59.5728. PMID: 26014290
  27. Boursi, B, et al. The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews. Eur. J. Cancer. 2013; 49(17):3680-5. PMID: 23896379
  28. Brand, R, et al. MUTYH-Associated Polyposis. 2012 Oct 04. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK107219/ PMID: 23035301
  29. Brandi, ML, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J. Clin. Endocrinol. Metab. 2001; 86(12):5658-71. doi: 10.1210/jcem.86.12.8070. PMID: 11739416
  30. Breast, Cancer, Linkage, Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 1999; 91(15):1310-6. doi: 10.1093/jnci/91.15.1310. PMID: 10433620
  31. Briggs, S, Tomlinson, I. Germline and somatic polymerase ε and ō mutations define a new class of hypermutated colorectal and endometrial cancers. J. Pathol. 2013; 230(2):148-53. doi: 10.1002/path.4185. PMID: 23447401
  32. Broderick, P, et al. Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC Cancer. 2006; 6:243. PMID: 17029639
  33. Broderick, P, et al. Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review. Gastroenterology. 2017; 152(1):75-77.e4. PMID: 27713038
  34. Brosens, LA, et al. Risk of colorectal cancer in juvenile polyposis. Gut. 2007; 56(7):965-7. doi: 10.1136/gut.2006.116913. PMID: 17303595
  35. Buffet, A, et al. A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. Horm. Metab. Res. 2012; 44(5):359-66. PMID: 22517557
  36. Burnichon, N, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 2010; 19(15):3011-20. doi: 10.1093/hmg/ddq206. PMID: 20484225
  37. Burt, RW, et al. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology. 2004; 127(2):444-51. PMID: 15300576
  38. Cai, Q, et al. Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget. 2015; 6(39):42312-21. PMID: 26517352
  39. Carballo, M, et al. Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am. J. Med. Genet. A. 2005; 132A(4):361-4. doi: 10.1002/ajmg.a.30388. PMID: 15742474
  40. Casadei S, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011 Mar 15;71(6):2222-9. PMID: 21285249
  41. Cassol, C, Mete, O. Endocrine manifestations of von Hippel-Lindau disease. Arch. Pathol. Lab. Med. 2015; 139(2):263-8. doi: 10.5858/arpa.2013-0520-RS. PMID: 25611110
  42. Castéra, L, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur. J. Hum. Genet. 2014; 22(11):1305-13. doi: 10.1038/ejhg.2014.16. PMID: 24549055
  43. Caux, F, et al. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Eur. J. Hum. Genet. 2007; 15(7):767-73. PMID: 17392703
  44. Chenevix-Trench, G, et al. Dominant negative ATM mutations in breast cancer families. J. Natl. Cancer Inst. 2002; 94(3):205-15. PMID: 11830610
  45. Cheng, HH, et al. A Pilot Study of Clinical Targeted Next Generation Sequencing for Prostate Cancer: Consequences for Treatment and Genetic Counseling. Prostate. 2016; 76(14):1303-1311. PMID: 27324988
  46. Chompret, A, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer. 2000; 82(12):1932-7. doi: 10.1054/bjoc.2000.1167. PMID: 10864200
  47. Chompret, A, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. 2004; 126(1):318-21. doi: 10.1053/j.gastro.2003.10.079. PMID: 14699510
  48. Chow, E, Macrae, F. A review of juvenile polyposis syndrome. J. Gastroenterol. Hepatol. 2005; 20(11):1634-40. doi: 10.1111/j.1440-1746.2005.03865.x. PMID: 16246179
  49. Chubb, D, et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J. Clin. Oncol. 2015; 33(5):426-32. doi: 10.1200/JCO.2014.56.5689. PMID: 25559809
  50. Church, JM. Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Dis. Colon Rectum. 2014; 57(3):396-7. doi: 10.1097/DCR.0000000000000084. PMID: 24509466
  51. Ciara, E, et al. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 2010; 119(3):325-34. PMID: 19908051
  52. Cleary, SP, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009; 136(4):1251-60. PMID: 19245865
  53. Coulet, F, et al. Germline RAD51C mutations in ovarian cancer susceptibility. Clin. Genet. 2013; 83(4):332-6. doi: 10.1111/j.1399-0004.2012.01917.x. PMID: 22725699
  54. Cybulski, C, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet. 2004; 75(6):1131-5. PMID: 15492928
  55. Cybulski, C, et al. NBS1 is a prostate cancer susceptibility gene. Cancer Res. 2004; 64(4):1215-9. doi: 10.1158/0008-5472.can-03-2502. PMID: 14973119
  56. Cybulski, C, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J. Clin. Oncol. 2011; 29(28):3747-52. doi: 10.1200/JCO.2010.34.0778. PMID: 21876083
  57. Damiola, F, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast Cancer Res. 2014; 16(3):R58. doi: 10.1186/bcr3669. PMID: 24894818
  58. Davis, H, et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 2015; 21(1):62-70. doi: 10.1038/nm.3750. PMID: 25419707
  59. De, Brakeleer, S, et al. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum. Mutat. 2010; 31(3):E1175-85. doi: 10.1002/humu.21200. PMID: 20077502
  60. Debniak, T, et al. A common variant of CDKN2A (p16) predisposes to breast cancer. J. Med. Genet. 2005; 42(10):763-5. doi: 10.1136/jmg.2005.031476. PMID: 15879498
  61. Dowty, JG, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum. Mutat. 2013; 34(3):490-7. doi: 10.1002/humu.22262. PMID: 23255516
  62. Dwight, T, et al. Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am. J. Surg. Pathol. 2013; 37(2):226-33. doi: 10.1097/PAS.0b013e3182671155. PMID: 23060355
  63. Dzikiewicz-Krawczyk, A. The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer. Mutat. Res. 2008; 659(3):262-73. PMID: 18606567
  64. Easton, DF, et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J. Med. Genet. 2016; :None. PMID: 26921362
  65. Ebi, H, et al. Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of cancer. Cancer Res. 2007; 67(23):11158-65. doi: 10.1158/0008-5472.CAN-07-1749. PMID: 18056440
  66. Elsayed, FA, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur. J. Hum. Genet. 2014; :None. doi: 10.1038/ejhg.2014.242. PMID: 25370038
  67. Eng, C. PTEN Hamartoma Tumor Syndrome (PHTS). 2001 Nov 29. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1488/ PMID: 20301661
  68. Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 2003; 22(3):183-98. PMID: 12938083
  69. Engel, C, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J. Clin. Oncol. 2012; 30(35):4409-15. doi: 10.1200/JCO.2012.43.2278. PMID: 23091106
  70. Ericson, KM, et al. Low frequency of defective mismatch repair in a population-based series of upper urothelial carcinoma. BMC Cancer. 2005; 5:23. PMID: 15740628
  71. Erkko, H, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007; 446(7133):316-9. PMID: 17287723
  72. Erkko, H, et al. Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin. Cancer Res. 2008; 14(14):4667-71. doi: 10.1158/1078-0432.CCR-08-0210. PMID: 18628482
  73. Esteban-Jurado, C, et al. New genes emerging for colorectal cancer predisposition. World J. Gastroenterol. 2014; 20(8):1961-71. doi: 10.3748/wjg.v20.i8.1961. PMID: 24587672
  74. Evans, DG, et al. Risk of breast cancer in male BRCA2 carriers. J. Med. Genet. 2010; 47(10):710-1. doi: 10.1136/jmg.2009.075176. PMID: 20587410
  75. Ewing, CM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N. Engl. J. Med. 2012; 366(2):141-9. PMID: 22236224
  76. Falchetti, A, et al. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet. Med. 2009; 11(12):825-35. doi: 10.1097/GIM.0b013e3181be5c97. PMID: 19904212
  77. Fitzgerald, RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J. Med. Genet. 2010; 47(7):436-44. doi: 10.1136/jmg.2009.074237. PMID: 20591882
  78. Ford, D, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 1998; 62(3):676-89. doi: 10.1086/301749. PMID: 9497246
  79. Ford, D, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994; 343(8899):692-5. doi: 10.1136/jmg.31.6.504-d. PMID: 7907678
  80. Foulkes, WD, et al. No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J. Pathol. 2014; 233(3):209-14. doi: 10.1002/path.4362. PMID: 24752781
  81. Frantzen, C, et al. Von Hippel-Lindau Syndrome. 2000 May 17. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1463/ PMID: 20301636
  82. Frazier, TW, et al. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Mol. Psychiatry. 2015; 20(9):1132-8. PMID: 25288137
  83. Friedl, W, et al. Attenuated familial adenomatous polyposis due to a mutation in the 3' part of the APC gene. A clue for understanding the function of the APC protein. Hum. Genet. 1996; 97(5):579-84. PMID: 8655134
  84. Gao, P, et al. Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies. Mutagenesis. 2013; 28(6):683-97. PMID: 24113799
  85. Giardiello, FM, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am. J. Gastroenterol. 2014; 109(8):1159-79. doi: 10.1038/ajg.2014.186. PMID: 25070057
  86. Giardiello, FM, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993; 34(10):1394-6. doi: 10.1136/gut.34.10.1394. PMID: 8244108
  87. Giri, VN, et al. Inherited Mutations in Men Undergoing Multigene Panel Testing for Prostate Cancer: Emerging Implications for Personalized Prostate Cancer Genetic Evaluation. JCO Precision Oncology, 2017
  88. Goh, S, et al. Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology. 2005; 65(2):235-8. PMID: 16043792
  89. Goldgar, DE, et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011; 13(4):R73. PMID: 21787400
  90. Goldstein, AM, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J. Med. Genet. 2007; 44(2):99-106. doi: 10.1136/jmg.2006.043802. PMID: 16905682
  91. Goldstein, AM, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006; 66(20):9818-28. doi: 10.1158/0008-5472.CAN-06-0494. PMID: 17047042
  92. Gonzalez, KD, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J. Med. Genet. 2009; 46(10):689-93. PMID: 19556618
  93. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  94. Groen, EJ, et al. Extra-intestinal manifestations of familial adenomatous polyposis. Ann. Surg. Oncol. 2008; 15(9):2439-50. doi: 10.1245/s10434-008-9981-3. PMID: 18612695
  95. Gronwald, J, et al. Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband. Br. J. Cancer. 2009; 100(9):1508-12. PMID: 19401704
  96. Hale, V, et al. CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer. Prostate Cancer. 2014; 2014:294575. PMID: 25431674
  97. Half, E, et al. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009; 4:22. doi: 10.1186/1750-1172-4-22. PMID: 19822006
  98. Han, FF, et al. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol. 2013; 32(6):329-35. doi: 10.1089/dna.2013.1970. PMID: 23713947
  99. Hansford, S, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015; 1(1):23-32. doi: 10.1001/jamaoncol.2014.168. PMID: 26182300
  100. Harinck, F, et al. Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas. J. Med. Genet. 2012; 49(6):362-5. PMID: 22636603
  101. Hearle, N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin. Cancer Res. 2006; 12(10):3209-15. PMID: 16707622
  102. Heikkinen, K, et al. Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. J. Med. Genet. 2003; 40(12):e131. doi: 10.1136/jmg.40.12.e131. PMID: 14684699
  103. Heikkinen, K, et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis. 2006; 27(8):1593-9. doi: 10.1093/carcin/bgi360. PMID: 16474176
  104. Helgadottir, H, et al. High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families. J. Med. Genet. 2014; 51(8):545-52. PMID: 24935963
  105. Helgason, H, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat. Genet. 2015; 47(8):906-10. PMID: 26098866
  106. Hendriks, YM, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 2004; 127(1):17-25. PMID: 15236168
  107. Hill, DA, et al. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009; 325(5943):965. PMID: 19556464
  108. Hirota, S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. PMID: 9438854
  109. Hoffmann, TJ, et al. Imputation of the rare HOXB13 G84E mutation and cancer risk in a large population-based cohort. PLoS Genet. 2015; 11(1):e1004930. PMID: 25629170
  110. Hopper, JL, et al. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol. Biomarkers Prev. 1999; 8(9):741-7. PMID: 10498392
  111. Hu, C, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. Cancer Epidemiol. Biomarkers Prev. 2015; :None. PMID: 26483394
  112. Huang, H, Cai, B. G84E mutation in HOXB13 is firmly associated with prostate cancer risk: a meta-analysis. Tumour Biol. 2014; 35(2):1177-82. PMID: 24026887
  113. Iqbal, J, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer. 2012; 107(12):2005-9. doi: 10.1038/bjc.2012.483. PMID: 23099806
  114. Italiano, A, et al. SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors. BMC Cancer. 2012; 12:408. doi: 10.1186/1471-2407-12-408. PMID: 22974104
  115. Jaeger, E, et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat. Genet. 2012; 44(6):699-703. doi: 10.1038/ng.2263. PMID: 22561515
  116. Janeway, KA, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc. Natl. Acad. Sci. U.S.A. 2011; 108(1):314-8. doi: 10.1073/pnas.1009199108. PMID: 21173220
  117. Jasperson, KW, Burt, RW. APC-Associated Polyposis Conditions. 1998 Dec 18. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301519
  118. Jelinic, P, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat. Genet. 2014; 46(5):424-6. PMID: 24658004
  119. Jenkins, MA, et al. Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol. Biomarkers Prev. 2006; 15(2):312-4. PMID: 16492921
  120. Jiang, Q, et al. A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma. Int J Clin Exp Pathol. 2015; 8(10):12188-97. PMID: 26722403
  121. Joinson, C, et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med. 2003; 33(2):335-44. PMID: 12622312
  122. Jones, N, et al. Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009; 137(2):489-94, 494.e1; quiz 725-6. PMID: 19394335
  123. Jones, S, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009; 324(5924):217. doi: 10.1126/science.1171202. PMID: 19264984
  124. Karlsson, R, et al. A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk. Eur. Urol. 2014; 65(1):169-76. PMID: 22841674
  125. Karppinen, SM, et al. Nordic collaborative study of the BARD1 Cys557Ser allele in 3956 patients with cancer: enrichment in familial BRCA1/BRCA2 mutation-negative breast cancer but not in other malignancies. J. Med. Genet. 2006; 43(11):856-62. doi: 10.1136/jmg.2006.041731. PMID: 16825437
  126. Kastrinos, F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009; 302(16):1790-5. doi: 10.1001/jama.2009.1529. PMID: 19861671
  127. Kaurah, P, Huntsman, DG. Hereditary Diffuse Gastric Cancer. 2002 Nov 04. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1139/ PMID: 20301318
  128. Kaurah, P, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007; 297(21):2360-72. doi: 10.1001/jama.297.21.2360. PMID: 17545690
  129. Kempers, MJ, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 2011; 12(1):49-55. doi: 10.1016/S1470-2045(10)70265-5. PMID: 21145788
  130. King, MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003; 302(5645):643-6. doi: 10.1126/science.1088759. PMID: 14576434
  131. Kohlmann, W, Gruber, SB. Lynch Syndrome. 2004 Feb 05. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390
  132. Korpershoek, E, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J. Clin. Endocrinol. Metab. 2011; 96(9):E1472-6. PMID: 21752896
  133. Kote-Jarai, Z, et al. Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes. Ann. Oncol. 2015; 26(4):756-61. PMID: 25595936
  134. Kuiper, RP, Hoogerbrugge, N. NTHL1 defines novel cancer syndrome. Oncotarget. 2015; 6(33):34069-70. PMID: 26431160
  135. Laken, SJ, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat. Genet. 1997; 17(1):79-83. PMID: 9288102
  136. Lammi, L, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am. J. Hum. Genet. 2004; 74(5):1043-50. doi: 10.1086/386293. PMID: 15042511
  137. Le, Calvez-Kelm, F, et al. RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study. PLoS ONE. 2012; 7(12):e52374. PMID: 23300655
  138. Lejeune, S, et al. Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis. Hum. Mutat. 2006; 27(10):1064. PMID: 16941501
  139. Leoz, ML, et al. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. Appl Clin Genet. 2015; 8:95-107. doi: 10.2147/TACG.S51484. PMID: 25931827
  140. Leslie, NR, Longy, M. Inherited PTEN mutations and the prediction of phenotype. Semin. Cell Dev. Biol. 2016; 52:30-8. PMID: 26827793
  141. Li, D, et al. The role of BRCA1 and BRCA2 in prostate cancer. Front Biosci (Landmark Ed). 2013; 18:1445-59. PMID: 23747895
  142. Li, J, et al. Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. Am. J. Hum. Genet. 2016; 98(5):830-42. PMID: 27087319
  143. Liang, J, et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am. J. Epidemiol. 2013; 177(11):1169-79. PMID: 23576677
  144. Liede, A, et al. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J. Clin. Oncol. 2004; 22(4):735-42. PMID: 14966099
  145. Liu, C, et al. The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pac. J. Cancer Prev. 2012; 13(4):1355-60. PMID: 22799331
  146. Loveday, C, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat. Genet. 2012; 44(5):475-6; author reply 476. PMID: 22538716
  147. Loveday, C, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat. Genet. 2011; 43(9):879-82. PMID: 21822267
  148. Lubbe, SJ, et al. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J. Clin. Oncol. 2009; 27(24):3975-80. doi: 10.1200/JCO.2008.21.6853. PMID: 19620482
  149. MacInnis, RJ, et al. Population-based estimate of prostate cancer risk for carriers of the HOXB13 missense mutation G84E. PLoS ONE. 2013; 8(2):e54727. PMID: 23457453
  150. Mahdi, H, et al. Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study. Cancer. 2015; 121(5):688-96. PMID: 25376524
  151. Maher, ER, et al. von Hippel-Lindau disease: a clinical and scientific review. Eur. J. Hum. Genet. 2011; 19(6):617-23. doi: 10.1038/ejhg.2010.175. PMID: 21386872
  152. Majewski, IJ, et al. An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J. Pathol. 2013; 229(4):621-9. doi: 10.1002/path.4152. PMID: 23208944
  153. Marsh, DJ, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum. Mol. Genet. 1999; 8(8):1461-72. PMID: 10400993
  154. Marvin, ML, et al. AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome. Am. J. Med. Genet. A. 2011; 155A(4):898-902. doi: 10.1002/ajmg.a.33927. PMID: 21416598
  155. Masciari, S, et al. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet. Med. 2011; 13(7):651-7. doi: 10.1097/GIM.0b013e31821628b6. PMID: 21552135
  156. Mazzoni, SM, et al. An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function. Neoplasia. 2015; 17(5):463-72. doi: 10.1016/j.neo.2015.04.006. PMID: 26025668
  157. McGarrity, TJ, et al. Peutz-Jeghers Syndrome. 2001 Feb 23. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1266/ PMID: 20301443
  158. McWilliams, RR, et al. Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur. J. Hum. Genet. 2011; 19(4):472-8. PMID: 21150883
  159. Meindl, A, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Genet. 2010; 42(5):410-4. PMID: 20400964
  160. Mester, J, Charis, E. PTEN hamartoma tumor syndrome. Handb Clin Neurol. 2015; 132:129-37. PMID: 26564076
  161. Mester, J, Eng, C. Cowden syndrome: recognizing and managing a not-so-rare hereditary cancer syndrome. J Surg Oncol. 2015; 111(1):125-30. PMID: 25132236
  162. Metcalfe, K, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J. Clin. Oncol. 2004; 22(12):2328-35. doi: 10.1200/JCO.2004.04.033. PMID: 15197194
  163. Miedlich, S, et al. Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant?. Eur. J. Endocrinol. 2001; 145(2):155-60. PMID: 11454510
  164. Miettinen, M, Lasota, J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int. J. Biochem. Cell Biol. 2014; 53:514-9. doi: 10.1016/j.biocel.2014.05.033. PMID: 24886695
  165. Minion, LE, et al. Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2. Gynecol. Oncol. 2015; 137(1):86-92. doi: 10.1016/j.ygyno.2015.01.537. PMID: 25622547
  166. Mohelnikova-Duchonova, B, et al. CHEK2 gene alterations in the forkhead-associated domain, 1100delC and del5395 do not modify the risk of sporadic pancreatic cancer. Cancer Epidemiol. 2010; 34(5):656-8. doi: 10.1016/j.canep.2010.06.008. PMID: 20643596
  167. Moran, A, et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam. Cancer. 2012; 11(2):235-42. PMID: 22187320
  168. Na, R, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur. Urol. 2017; 71(5):740-747. PMID: 27989354
  169. Nathan, N, et al. Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway. Dermatol Clin. 2017; 35(1):51-60. PMID: 27890237
  170. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed January 2018.
  171. National Library of Medicine Genetics Home Reference. Prostate cancer. http://ghr.nlm.nih.gov/condition/prostate-cancer. Accessed January 2018.
  172. Neklason, DW, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(1):46-52. PMID: 18063416
  173. Neumann, HP, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004; 292(8):943-51. PMID: 15328326
  174. Ni, Y, et al. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum. Mol. Genet. 2012; 21(2):300-10. doi: 10.1093/hmg/ddr459. PMID: 21979946
  175. Ni, Y, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. 2008; 83(2):261-8. PMID: 18678321
  176. Northrup, H, et al. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol. 2013; 49(4):243-54. doi: 10.1016/j.pediatrneurol.2013.08.001. PMID: 24053982
  177. Norton, JA, et al. Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surg. Oncol. Clin. N. Am. 2015; 24(4):795-832. PMID: 26363542
  178. Obermair, A, et al. Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int. J. Cancer. 2010; 127(11):2678-84. PMID: 20533284
  179. Olivier, M, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003; 63(20):6643-50. PMID: 14583457
  180. Olsen, JH, et al. Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br. J. Cancer. 2005; 93(2):260-5. PMID: 15942625
  181. Osorio, A, et al. Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum. Mol. Genet. 2012; 21(13):2889-98. doi: 10.1093/hmg/dds115. PMID: 22451500
  182. Ow, GS, et al. Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. Cell Cycle. 2014; 13(14):2262-80. doi: 10.4161/cc.29271. PMID: 24879340
  183. Pachlopnik, Schmid, J, et al. Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome"). J. Exp. Med. 2012; 209(13):2323-30. PMID: 23230001
  184. Pakkanen, S, et al. PALB2 variants in hereditary and unselected Finnish prostate cancer cases. J Negat Results Biomed. 2009; 8:12. PMID: 20003494
  185. Palles, C, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 2013; 45(2):136-44. PMID: 23263490
  186. Pan, KF, et al. Mutations in components of the Wnt signaling pathway in gastric cancer. World J. Gastroenterol. 2008; 14(10):1570-4. doi: 10.3748/wjg.14.1570. PMID: 18330950
  187. Pannett, AA, et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2003; 58(5):639-46. doi: 10.1046/j.1365-2265.2003.01765.x. PMID: 12699448
  188. Pantaleo, MA, et al. Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST. Eur. J. Hum. Genet. 2014; 22(1):32-9. doi: 10.1038/ejhg.2013.80. PMID: 23612575
  189. Pantaleo, MA, et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J. Natl. Cancer Inst. 2011; 103(12):983-7. PMID: 21505157
  190. Pasini, B, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur. J. Hum. Genet. 2008; 16(1):79-88. doi: 10.1038/sj.ejhg.5201904. PMID: 17667967
  191. Peczkowska, M, et al. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab. 2008; 4(2):111-5. PMID: 18212813
  192. Pelttari, LM, et al. A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer. J. Med. Genet. 2012; 49(7):429-32. PMID: 22652533
  193. Pelttari, LM, et al. RAD51C is a susceptibility gene for ovarian cancer. Hum. Mol. Genet. 2011; 20(16):3278-88. PMID: 21616938
  194. Pharoah, PD, et al. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001; 121(6):1348-53. doi: 10.1053/gast.2001.29611. PMID: 11729114
  195. Phelan, CM, et al. Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study. Br. J. Cancer. 2014; 110(2):530-4. doi: 10.1038/bjc.2013.741. PMID: 24292448
  196. Pilarski, R, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J. Natl. Cancer Inst. 2013; 105(21):1607-16. PMID: 24136893
  197. Pollock, J, Welsh, JS. Clinical cancer genetics: Part I: Gastrointestinal. Am. J. Clin. Oncol. 2011; 34(3):332-6. doi: 10.1097/COC.0b013e3181dea432. PMID: 20859198
  198. Postow, MA, Robson, ME. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin Sarcoma Res. 2012; 2(1):16. doi: 10.1186/2045-3329-2-16. PMID: 23036227
  199. Poumpouridou, N, Kroupis, C. Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges. Clin. Chem. Lab. Med. 2012; 50(3):423-34. doi: 10.1515/cclm-2011-0840. PMID: 22505525
  200. Pritchard, CC. et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. NEJM, 2016 PMID: 27433846
  201. Rafnar, T, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat. Genet. 2011; 43(11):1104-7. PMID: 21964575
  202. Rahman, N, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 2007; 39(2):165-7. doi: 10.1038/ng1959. PMID: 17200668
  203. Ramos, P, et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat. Genet. 2014; 46(5):427-9. doi: 10.1038/ng.2928. PMID: 24658001
  204. Ramus, SJ, et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J. Natl. Cancer Inst. 2015; 107(11):None. PMID: 26315354
  205. Ratajska, M, et al. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res. Treat. 2012; 131(1):89-97. doi: 10.1007/s10549-011-1403-8. PMID: 21344236
  206. Raymond, VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J. Clin. Oncol. 2013; 31(14):1713-8. PMID: 23530095
  207. Rennert, G, et al. MutYH mutation carriers have increased breast cancer risk. Cancer. 2012; 118(8):1989-93. doi: 10.1002/cncr.26506. PMID: 21952991
  208. Renwick, A, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 2006; 38(8):873-5. doi: 10.1038/ng1837. PMID: 16832357
  209. Repak, R, et al. The first European family with gastric adenocarcinoma and proximal polyposis of the stomach: case report and review of the literature. Gastrointest. Endosc. 2016; 84(4):718-25. PMID: 27343414
  210. Resnick, IB, et al. 657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls. Am. J. Med. Genet. A. 2003; 120A(2):174-9. doi: 10.1002/ajmg.a.20188. PMID: 12833396
  211. Ricci, R, et al. PDGFRA-mutant syndrome. Mod. Pathol. 2015; 28(7):954-64. doi: 10.1038/modpathol.2015.56. PMID: 25975287
  212. Richards, FM, et al. Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum. Mol. Genet. 1999; 8(4):607-10. doi: 10.1093/hmg/8.4.607. PMID: 10072428
  213. Ricketts, C, et al. Germline SDHB mutations and familial renal cell carcinoma. J. Natl. Cancer Inst. 2008; 100(17):1260-2. doi: 10.1093/jnci/djn254. PMID: 18728283
  214. Ricketts, CJ, et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J. Urol. 2012; 188(6):2063-71. PMID: 23083876
  215. Riegert-Johnson, DL, et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010; 8(1):6. PMID: 20565722
  216. Rio, Frio, T, et al. DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA. 2011; 305(1):68-77. doi: 10.1001/jama.2010.1910. PMID: 21205968
  217. Rivera, B, et al. A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia. Eur. J. Hum. Genet. 2014; 22(3):423-6. doi: 10.1038/ejhg.2013.146. PMID: 23838596
  218. Rivera, B, et al. Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors. N. Engl. J. Med. 2015; 373(20):1985-6. PMID: 26559593
  219. Roberts, NJ, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012; 2(1):41-6. doi: 10.1158/2159-8290.CD-11-0194. PMID: 22585167
  220. Robson, ME, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J. Clin. Oncol. 2010; 28(5):893-901. PMID: 20065170
  221. Rohlin, A, et al. A mutation in POLE predisposing to a multi-tumour phenotype. Int. J. Oncol. 2014; 45(1):77-81. doi: 10.3892/ijo.2014.2410. PMID: 24788313
  222. Ruijs, MW, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J. Med. Genet. 2010; 47(6):421-8. PMID: 20522432
  223. Ryan, S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 2014; 23(3):437-49. PMID: 24425144
  224. Schiavi, F, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005; 294(16):2057-63. PMID: 16249420
  225. Schneider, K, et al. Li-Fraumeni Syndrome. 1999 Jan 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle. PMID: 20301488
  226. Seal, S, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 2006; 38(11):1239-41. PMID: 17033622
  227. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  228. Shepherd, CW, et al. Causes of death in patients with tuberous sclerosis. Mayo Clin. Proc. 1991; 66(8):792-6. PMID: 1861550
  229. Sieber, OM, et al. Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut. 2006; 55(10):1440-8. PMID: 16461775
  230. Skeldon, SC, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur. Urol. 2013; 63(2):379-85. PMID: 22883484
  231. Slade, I, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J. Med. Genet. 2011; 48(4):273-8. doi: 10.1136/jmg.2010.083790. PMID: 21266384
  232. Slater, EP, et al. PALB2 mutations in European familial pancreatic cancer families. Clin. Genet. 2010; 78(5):490-4. doi: 10.1111/j.1399-0004.2010.01425.x. PMID: 20412113
  233. Smith, CG, et al. Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer. Hum. Mutat. 2013; 34(7):1026-34. doi: 10.1002/humu.22333. PMID: 23585368
  234. Song, H, et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J. Clin. Oncol. 2015; :None. PMID: 26261251
  235. Southey, MC, et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J. Med. Genet. 2016; :None. PMID: 27595995
  236. Spier, I, et al. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int. J. Cancer. 2015; 137(2):320-31. PMID: 25529843
  237. Spirio, L, et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. 1993; 75(5):951-7. doi: 10.1016/0092-8674(93)90538-2. PMID: 8252630
  238. Sredni, ST, Tomita, T. Rhabdoid tumor predisposition syndrome. Pediatr. Dev. Pathol. 2015; 18(1):49-58. doi: 10.2350/14-07-1531-MISC.1. PMID: 25494491
  239. Stadler, ZK, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer. 2012; 118(2):493-9. doi: 10.1002/cncr.26191. PMID: 21598239
  240. Steffen, J, et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int. J. Cancer. 2006; 119(2):472-5. PMID: 16770759
  241. Steffen, J, et al. Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int. J. Cancer. 2004; 111(1):67-71. doi: 10.1002/ijc.20239. PMID: 15185344
  242. Stenzinger, A, et al. Mutations in POLE and survival of colorectal cancer patients–link to disease stage and treatment. Cancer Med. 2014; 3(6):1527-38. doi: 10.1002/cam4.305. PMID: 25124163
  243. Stott-Miller, M, et al. HOXB13 mutations in a population-based, case-control study of prostate cancer. Prostate. 2013; 73(6):634-41. PMID: 23129385
  244. Struewing, JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N. Engl. J. Med. 1997; 336(20):1401-8. PMID: 9145676
  245. Syngal, S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 2015; 110(2):223-62; quiz 263. doi: 10.1038/ajg.2014.435. PMID: 25645574
  246. Tai, YC, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J. Natl. Cancer Inst. 2007; 99(23):1811-4. doi: 10.1093/jnci/djm203. PMID: 18042939
  247. Tan, MH, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 2012; 18(2):400-7. doi: 10.1158/1078-0432.CCR-11-2283. PMID: 22252256
  248. Teodorczyk, U, et al. The risk of gastric cancer in carriers of CHEK2 mutations. Fam. Cancer. 2013; 12(3):473-8. doi: 10.1007/s10689-012-9599-2. PMID: 23296741
  249. Thakker, RV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 2012; 97(9):2990-3011. doi: 10.1210/jc.2012-1230. PMID: 22723327
  250. Thakker, RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell. Endocrinol. 2014; 386(1-2):2-15. doi: 10.1016/j.mce.2013.08.002. PMID: 23933118
  251. Thakker, RV. Multiple endocrine neoplasia type 1. Indian J Endocrinol Metab. 2012; 16(Suppl 2):S272-4. PMID: 23565397
  252. Thiffault, I, et al. A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes. BMC Med. Genet. 2015; 16:31. PMID: 25948378
  253. Thompson, D, et al. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol. Biomarkers Prev. 2006; 15(12):2542-5. PMID: 17164383
  254. Thompson, D, et al. Cancer Incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 2002; 94(18):1358-65. doi: 10.1093/jnci/94.18.1358. PMID: 12237281
  255. Thompson, D, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J. Natl. Cancer Inst. 2005; 97(11):813-22. doi: 10.1093/jnci/dji141. PMID: 15928302
  256. Thompson, ER, et al. Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS ONE. 2013; 8(1):e54772. PMID: 23372765
  257. Tischkowitz, M, et al. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer. Prostate. 2008; 68(6):675-8. PMID: 18288683
  258. Toss, A, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. 2015; 2015:341723. doi: 10.1155/2015/341723. PMID: 26075229
  259. U.S. Department of Health and Human Services. What is Your Prostate? http://archive.ahrq.gov/patients-consumers/prevention/understanding/bodysys/edbody13.html, Accessed January 2018.
  260. Valle, L, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum. Mol. Genet. 2014; 23(13):3506-12. doi: 10.1093/hmg/ddu058. PMID: 24501277
  261. Varga, EA, et al. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet. Med. 2009; 11(2):111-7. PMID: 19265751
  262. Vasen, HF, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013; 62(6):812-23. PMID: 23408351
  263. Vasen, HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int. J. Cancer. 2000; 87(6):809-11. doi: 10.1016/s0016-5085(00)84701-0. PMID: 10956390
  264. Vaz, F, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat. Genet. 2010; 42(5):406-9. PMID: 20400963
  265. Villablanca, A, et al. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur. J. Endocrinol. 2002; 147(3):313-22. PMID: 12213668
  266. Vogt, S, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009; 137(6):1976-85.e1-10. doi: 10.1053/j.gastro.2009.08.052. PMID: 19732775
  267. Walsh, T, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc. Natl. Acad. Sci. U.S.A. 2011; 108(44):18032-7. doi: 10.1073/pnas.1115052108. PMID: 22006311
  268. Wasielewski, M, et al. CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res. Treat. 2009; 116(2):397-400. PMID: 18759107
  269. Watson, GA, et al. Get the GIST? An overview of gastrointestinal stromal tumours. Ir J Med Sci. 2016; :None. PMID: 26833487
  270. Weedon, MN, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat. Genet. 2013; 45(8):947-50. doi: 10.1038/ng.2670. PMID: 23770608
  271. Weischer, M, et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J. Clin. Oncol. 2008; 26(4):542-8. doi: 10.1200/JCO.2007.12.5922. PMID: 18172190
  272. Weren, RD, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat. Genet. 2015; :None. PMID: 25938944
  273. Williamson, SR, et al. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod. Pathol. 2015; 28(1):80-94. PMID: 25034258
  274. Win, AK, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int. J. Cancer. 2011; 129(9):2256-62. doi: 10.1002/ijc.25870. PMID: 21171015
  275. Win, AK, et al. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology. 2014; 146(5):1208-11.e1-5. PMID: 24444654
  276. Witkowski, L, et al. Familial rhabdoid tumour 'avant la lettre'--from pathology review to exome sequencing and back again. J. Pathol. 2013; 231(1):35-43. PMID: 23775540
  277. Witkowski, L, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat. Genet. 2014; 46(5):438-43. doi: 10.1038/ng.2931. PMID: 24658002
  278. Wong, P, et al. Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology. 2006; 130(1):73-9. doi: 10.1053/j.gastro.2005.10.014. PMID: 16401470
  279. Wong, S, et al. Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia. Arch. Oral Biol. 2014; 59(3):349-53. PMID: 24581859
  280. Worthley, DL, et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut. 2012; 61(5):774-9. PMID: 21813476
  281. Wu, Y, et al. DICER1 mutations in a patient with an ovarian Sertoli-Leydig tumor, well-differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter. Eur J Med Genet. 2014; 57(11-12):621-5. doi: 10.1016/j.ejmg.2014.09.008. PMID: 25451712
  282. Xiang, HP, et al. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur. J. Cancer. 2011; 47(17):2546-51. PMID: 21807500
  283. Xu, J, et al. HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum. Genet. 2013; 132(1):5-14. PMID: 23064873
  284. Zhang, B, et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011; 12(5):477-88. PMID: 21514219
  285. de, Raedt, T, et al. Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology. 2006; 131(6):1907-12. doi: 10.1053/j.gastro.2006.07.002. PMID: 17087943
  286. di, Masi, A, Antoccia, A. NBS1 Heterozygosity and Cancer Risk. Curr. Genomics. 2008; 9(4):275-81. doi: 10.2174/138920208784533610. PMID: 19452044
  287. van, Asperen, CJ, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J. Med. Genet. 2005; 42(9):711-9. PMID: 16141007
  288. van, Lier, MG, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am. J. Gastroenterol. 2010; 105(6):1258-64; author reply 1265. PMID: 20051941
  289. van, Os, NJ, et al. Health risks for ataxia-telangiectasia mutated heterozygotes: A systematic review, Meta-analysis and evidence-based guideline. Clin. Genet. 2015; :None. PMID: 26662178
  290. van, der, Luijt, RB, et al. APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. Hum. Genet. 1995; 96(6):705-10. PMID: 8522331
  291. van, der, Post, RS, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J. Med. Genet. 2015; 52(6):361-74. doi: 10.1136/jmedgenet-2015-103094. PMID: 25979631

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