Ordering
  • Test code: 01271
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit
Billing
 
Print this page
  1. Test Catalog
  2. Invitae Gastric Cancer Panel

Invitae Gastric Cancer Panel

Test description

The Invitae Gastric Cancer Panel analyzes genes associated with an increased lifetime risk of developing stomach cancer. These genes were selected based on the available evidence to date to provide Invitae’s broadest hereditary gastric cancer test. Many of these genes are also associated with an increased risk of other cancer types.

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 BMPR1A CDH1 CTNNA1 EPCAM KIT MLH1 MSH2 MSH6 NF1 PDGFRA PMS2 SDHA SDHB SDHC SDHD SMAD4 STK11 TP53

Order test

Primary panel (19 genes)

APC BMPR1A CDH1 CTNNA1 EPCAM KIT MLH1 MSH2 MSH6 NF1 PDGFRA PMS2 SDHA SDHB SDHC SDHD SMAD4 STK11 TP53

Panel details and technical assay limitations

Alternative tests to consider

These genes can also be ordered as part of broader, cross-cancer, multi-gene panels. Depending on the individual’s clinical and family history, these broader panels may be appropriate and can be ordered at no additional charge.

Clinical information

  • constitutional mismatch repair deficiency (CMMR-D)
  • familial adenomatous polyposis (FAP)
  • familial gastrointestinal stromal tumor (GIST)
  • hereditary diffuse gastric cancer syndrome (HDGC)
  • hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC)
  • juvenile polyposis syndrome (JPS)
  • Li-Fraumeni syndrome (LFS)
  • Lynch syndrome – also known as hereditary non-polyposis colorectal cancer (HNPCC)
  • neurofibromatosis type 1 (NF1)
  • Peutz-Jeghers syndrome (JPS)

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. One of the most common causes 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. It is important to note that GISTs are not the same as gastric adenocarcinomas; they differ in their pathology, prognosis, and medical management.

Most cases of gastric cancer are sporadic; however, approximately 3%-5% have a familial component and are due to an identifiable pathogenic variant. The Invitae Gastric Cancer panel tests for:

  • hereditary conditions associated with intestinal-type gastric adenocarcinomas such as Lynch and Peutz-Jeghers syndromes
  • hereditary diffuse gastric cancer syndrome due to pathogenic variants in CDH1, a gene that is associated with diffuse-type adenocarcinomas
  • familial GIST, which is associated with a subset of genes

In individuals with a pathogenic variant in one of these genes, the risk of developing cancer is significantly higher, and many of these cancers may be difficult to detect and/or treat. Identifying those at higher risk may enable additional screening, surveillance, and interventions, which could result in risk-reduction and early diagnosis, thereby increasing the chances of successful treatment and survival.

Individuals with a pathogenic variant in one of these genes 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.

Most of the genes on this panel have autosomal dominant inheritance for hereditary gastric cancer. Some have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions, as outlined below:

  • MUTYH is associated with MUTYH-associated polyposis (MAP)
  • MLH1, MSH2, MSH6, and PMS2 are associated with constitutional mismatch repair deficiency (CMMR-D)

This panel may be considered for individuals whose personal and/or family history is suggestive of a hereditary gastric cancer syndrome, including:

  • gastric cancer, particularly if early-onset
  • gastric cancer in multiple relatives on the same side of the family
  • gastric and breast cancer (particularly lobular type) in the same individual or family
  • gastric and other GI tumors in one individual or family
  • gastric polyposis
    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., breast cancer in a man)

  1. 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
  2. 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
  3. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  4. Zöller, ME, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer. 1997; 79(11):2125-31. doi: 10.1002/(sici)1097-0142(19970601)79:11<2125::aid-cncr9>3.0.co;2-n. PMID: 9179058
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. Agaimy, A, et al. Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen's disease): clinicopathological spectrum with pathogenetic considerations. Int J Clin Exp Pathol. 2012; 5(9):852-62. PMID: 23119102
  19. 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
  20. 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
  21. Ricci, R, et al. PDGFRA-mutant syndrome. Mod. Pathol. 2015; 28(7):954-64. doi: 10.1038/modpathol.2015.56. PMID: 25975287
  22. 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
  23. 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
  24. 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
  25. Half, E, et al. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009; 4:22. doi: 10.1186/1750-1172-4-22. PMID: 19822006
  26. 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
  27. 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
  28. Evans, DG, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am. J. Med. Genet. A. 2010; 152A(2):327-32. doi: 10.1002/ajmg.a.33139. PMID: 20082463
  29. 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
  30. 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
  31. 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
  32. 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
  33. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  34. 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
  35. 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
  36. 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
  37. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Colorectal. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed September 2019.
  38. American Cancer Society, Lifetime Risks of Developing Various Cancers. http://www.cancer.org/cancer/cancerbasics/lifetime-probability-of-developing-or-dying-from-cancer Accessed August 2019..
  39. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian Version 3.2019. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed September 2019
  40. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Gastric Cancer. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed January 2018.
  41. American Society of Clinical Oncology, Cancer.Net. http://www.cancer.net/cancer-types/hereditary-diffuse-gastric-cancer Accessed September 2019.
  42. Walker, L, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br. J. Cancer. 2006; 95(2):233-8. doi: 10.1038/sj.bjc.6603227. PMID: 16786042
  43. 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
  44. 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
  45. Aarnio, M, et al. Uroepithelial and kidney carcinoma in Lynch syndrome. Fam. Cancer. 2012; 11(3):395-401. PMID: 22476430
  46. 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
  47. 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
  48. Benn, DE, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 2006; 91(3):827-36. PMID: 16317055
  49. 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
  50. Neklason, DW, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(1):46-52. PMID: 18063416
  51. 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
  52. 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
  53. 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
  54. Bisgaard, ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat. 1994; 3(2):121-5. PMID: 8199592
  55. 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
  56. 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
  57. 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
  58. 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
  59. 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
  60. 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
  61. 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
  62. 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
  63. 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
  64. 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
  65. Hearle, N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin. Cancer Res. 2006; 12(10):3209-15. PMID: 16707622
  66. Gonzalez, KD, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J. Med. Genet. 2009; 46(10):689-93. PMID: 19556618
  67. Watson, GA, et al. Get the GIST? An overview of gastrointestinal stromal tumours. Ir J Med Sci. 2016; :None. PMID: 26833487
  68. Hirota, S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. PMID: 9438854
  69. 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
  70. 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
  71. 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
  72. 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
  73. 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
  74. 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
  75. 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
  76. Easton, DF, et al. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am. J. Hum. Genet. 1993; 53(2):305-13. PMID: 8328449
  77. 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
  78. 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
  79. 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
  80. 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
  81. 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
  82. Gorgel, A, et al. Coexistence of gastrointestinal stromal tumors (GISTs) and pheochromocytoma in three cases of neurofibromatosis type 1 (NF1) with a review of the literature. Intern. Med. 2014; 53(16):1783-9. doi: 10.2169/internalmedicine.53.2012. PMID: 25130111
  83. 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
  84. 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
  85. 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
  86. Seminog, OO, Goldacre, MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br. J. Cancer. 2013; 108(1):193-8. PMID: 23257896
  87. 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
  88. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  89. 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
  90. 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
  91. Schneider, K, et al. Li-Fraumeni Syndrome. 1999 Jan 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle. PMID: 20301488
  92. Aarnio, M. Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012; 2012:350309. doi: 10.1155/2012/350309. PMID: 22619739
  93. 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
  94. Stratakis, CA, Carney, JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J. Intern. Med. 2009; 266(1):43-52. doi: 10.1111/j.1365-2796.2009.02110.x. PMID: 19522824
  95. 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
  96. 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

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

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
BMPR1A* NM_004329.2
CDH1 NM_004360.3
CTNNA1 NM_001903.3
EPCAM* NM_002354.2
KIT NM_000222.2
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH6 NM_000179.2
NF1* NM_000267.3
PDGFRA NM_006206.4
PMS2 NM_000535.5
SDHA* NM_004168.3
SDHB NM_003000.2
SDHC NM_003001.3
SDHD NM_003002.3
SMAD4 NM_005359.5
STK11 NM_000455.4
TP53* NM_000546.5

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.
EPCAM: Analysis is limited to deletion/duplication analysis.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).
NF1: Sequencing analysis for exons 41, 48 includes only cds +/- 10 bp.
SDHA: Deletion/duplication analysis is not offered for this gene. Sequencing analysis for exons 6-8, 14 includes only cds +/- 10 bp.
TP53: Deletion/duplication analysis covers the promoter region.

Clinical resources
Genes and associated cancers chart Hereditary cancer requisition form and 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 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. Agaimy, A, et al. Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen's disease): clinicopathological spectrum with pathogenetic considerations. Int J Clin Exp Pathol. 2012; 5(9):852-62. PMID: 23119102
  5. American Cancer Society, Lifetime Risks of Developing Various Cancers. http://www.cancer.org/cancer/cancerbasics/lifetime-probability-of-developing-or-dying-from-cancer Accessed August 2019..
  6. American Society of Clinical Oncology, Cancer.Net. http://www.cancer.net/cancer-types/hereditary-diffuse-gastric-cancer Accessed September 2019.
  7. 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
  8. 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
  9. 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
  10. Benn, DE, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 2006; 91(3):827-36. PMID: 16317055
  11. 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
  12. Bisgaard, ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat. 1994; 3(2):121-5. PMID: 8199592
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. Easton, DF, et al. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am. J. Hum. Genet. 1993; 53(2):305-13. PMID: 8328449
  27. 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
  28. Evans, DG, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am. J. Med. Genet. A. 2010; 152A(2):327-32. doi: 10.1002/ajmg.a.33139. PMID: 20082463
  29. 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
  30. 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
  31. 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
  32. 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
  33. Gonzalez, KD, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J. Med. Genet. 2009; 46(10):689-93. PMID: 19556618
  34. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  35. Gorgel, A, et al. Coexistence of gastrointestinal stromal tumors (GISTs) and pheochromocytoma in three cases of neurofibromatosis type 1 (NF1) with a review of the literature. Intern. Med. 2014; 53(16):1783-9. doi: 10.2169/internalmedicine.53.2012. PMID: 25130111
  36. 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
  37. Half, E, et al. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009; 4:22. doi: 10.1186/1750-1172-4-22. PMID: 19822006
  38. 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
  39. Hearle, N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin. Cancer Res. 2006; 12(10):3209-15. PMID: 16707622
  40. 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
  41. Hirota, S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. PMID: 9438854
  42. 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
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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
  52. 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
  53. 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
  54. 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
  55. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  56. 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
  57. 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
  58. 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
  59. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Gastric Cancer. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed January 2018.
  60. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian Version 3.2019. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed September 2019
  61. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Colorectal. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed September 2019.
  62. Neklason, DW, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(1):46-52. PMID: 18063416
  63. 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
  64. 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
  65. 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
  66. 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
  67. 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
  68. 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
  69. 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
  70. 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
  71. 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
  72. 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
  73. Ricci, R, et al. PDGFRA-mutant syndrome. Mod. Pathol. 2015; 28(7):954-64. doi: 10.1038/modpathol.2015.56. PMID: 25975287
  74. 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
  75. 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
  76. 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
  77. 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
  78. Schneider, K, et al. Li-Fraumeni Syndrome. 1999 Jan 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle. PMID: 20301488
  79. Seminog, OO, Goldacre, MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br. J. Cancer. 2013; 108(1):193-8. PMID: 23257896
  80. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  81. 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
  82. 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
  83. 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
  84. Stratakis, CA, Carney, JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J. Intern. Med. 2009; 266(1):43-52. doi: 10.1111/j.1365-2796.2009.02110.x. PMID: 19522824
  85. 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
  86. 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
  87. Walker, L, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br. J. Cancer. 2006; 95(2):233-8. doi: 10.1038/sj.bjc.6603227. PMID: 16786042
  88. Watson, GA, et al. Get the GIST? An overview of gastrointestinal stromal tumours. Ir J Med Sci. 2016; :None. PMID: 26833487
  89. 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
  90. 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
  91. 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
  92. Zöller, ME, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer. 1997; 79(11):2125-31. doi: 10.1002/(sici)1097-0142(19970601)79:11<2125::aid-cncr9>3.0.co;2-n. PMID: 9179058
  93. 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
  94. 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
  95. 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
  96. 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

Headquarters | 458 Brannan Street, San Francisco, CA 94107

Laboratory & Shipping | 475 Brannan Street, Suite 230, San Francisco, CA 94107 | www.invitae.com

In the US | clientservices@invitae.com | p: 800-436-3037 | f: 415-276-4164

Outside the US | globalsupport@invitae.com or visit www.invitae.com/contact

©2015 Invitae Corp. All rights reserved.