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  • Test code: 01251
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Colorectal Cancer Panel

Test description

The Invitae Colorectal Cancer Panel analyzes genes associated with a hereditary predisposition to colorectal cancer. These genes were selected based on the available evidence to date to provide Invitae’s broadest test for colorectal cancer.

The primary panel includes 20 genes associated with colorectal cancer. In addition to the primary panel, clinicians can also choose to include 10 genes that have preliminary evidence of an association with this cancer type. These genes were selected from a review of the literature and expert recommendations. At this time, the association of these genes with colorectal cancer remains uncertain; however, some clinicians may wish to include genes that may prove to be clinically significant in the future. These genes can be added at no additional charge.

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.

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Primary panel (20 genes)

APC AXIN2 BMPR1A CDH1 CHEK2 EPCAM GREM1 MLH1 MSH2 MSH3 MSH6 MUTYH NTHL1 PMS2 POLD1 POLE PTEN SMAD4 STK11 TP53

Add-on Preliminary-evidence Genes for Colorectal Cancer (10 genes)

Genes with preliminary evidence of association with hereditary colon cancer are available to add on to the primary panel. Adding on preliminary-evidence genes can increase the number of variants of uncertain significance that are identified. Some clinicians may wish to include genes that do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. Visit our Preliminary-evidence genes page to learn more.

ATM BLM BUB1B CEP57 ENG FLCN GALNT12 MLH3 RNF43 RPS20

Alternative tests to consider

These genes can also be ordered as 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.

  • Cowden and Cowden-like syndrome
  • Familial adenomatous polyposis (FAP)
  • Attenuated familial adenomatous polyposis (AFAP)
  • Constitutional mismatch repair deficiency (CMMR-D)
  • Hereditary diffuse gastric cancer (HDGC)
  • Juvenile polyposis syndrome (JPS)
  • Li-Fraumeni syndrome (LFS)
  • Lynch syndrome – also known as hereditary non-polyposis colorectal cancer (HNPCC)
  • MUTYH-associated polyposis (MAP)
  • Oligodontia-colorectal cancer syndrome
  • Peutz-Jeghers syndrome (PJS)

Colorectal cancer (CRC) is a malignancy of the large intestine (colon) and/or rectum. Hereditary colon 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. This condition is the most common inherited cause of colorectal cancer. Polyposis syndromes are characterized by the development of numerous precancerous polyps, which may become malignant.

Colorectal cancer is the third most common cancer diagnosis in the United States, with a general population risk of 4.8%. Up to 5% of heritable cases are due to Lynch syndrome, less than 1% are due to familial adenomatous polyposis (FAP) and less than 0.1% are due to hamartomatous polyposis syndromes, including juvenile polyposis syndrome (JPS), MUTYH-associated polyposis (MAP) and Peutz-Jeghers syndrome (PJS).

In addition to these conditions, this panel includes other hereditary colorectal cancer syndromes, many of which are also associated with other cancer types. Individuals who have inherited a pathogenic variant in one of these genes have an elevated risk of developing certain cancers, many of which may be difficult to detect and/or treat. Identifying those at high risk may enable additional screening, surveillance and interventions, which would 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. Several also have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions, as outlined below:

  • MSH3 is associated with MSH3-associated polyposis
  • NTHL1 is associated with NTHL1-associated polyposis
  • MUTYH is associated with MUTYH-associated polyposis (MAP)
  • MLH1, MSH2, MSH6, and PMS2 are associated with constitutional mismatch repair deficiency (CMMR-D)
  • POLE is associated with facial dysmorphism, immunodeficiency, livedo and short stature (FILS) syndrome

This panel may be appropriate for individuals with a personal history of colon cancer and/or a family history of suggestive of a hereditary colon cancer syndrome, including:

  • an early-onset colon cancer diagnosis at ≤50 years of age
  • multiple primary cancers, including colon cancer
  • colon cancer and a family history of other gastrointestinal or gynecologic malignancies
  • tumor testing shows mismatch repair deficiency (dMMR) (eg. MSI, IHC)
  • presence of an abnormally high number (10+) of precancerous colorectal polyps (adenomas)
  • multiple hamartomatous colorectal polyps
  • a clinical or family history that meets the criteria for evaluating specific hereditary colon cancer syndromes

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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. Half, E, et al. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009; 4:22. doi: 10.1186/1750-1172-4-22. PMID: 19822006
  31. Xiang, HP, et al. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur. J. Cancer. 2011; 47(17):2546-51. PMID: 21807500
  32. 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
  33. 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
  34. 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
  35. 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
  36. Aarnio, M. Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012; 2012:350309. doi: 10.1155/2012/350309. PMID: 22619739
  37. 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
  38. 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
  39. 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
  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. 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
  42. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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
  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. Bisgaard, ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat. 1994; 3(2):121-5. PMID: 8199592
  54. 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
  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. 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
  64. 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
  65. 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
  66. Cybulski, C, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet. 2004; 75(6):1131-5. PMID: 15492928
  67. 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
  68. 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
  69. 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
  70. 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
  71. 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
  72. 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
  73. 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
  74. 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
  75. 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
  76. Kuiper, RP, Hoogerbrugge, N. NTHL1 defines novel cancer syndrome. Oncotarget. 2015; 6(33):34069-70. PMID: 26431160
  77. Belhadj, S, et al. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis. Clin. Gastroenterol. Hepatol. 2017; 15(3):461-462. PMID: 27720914
  78. 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
  79. 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
  80. 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
  81. 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
  82. 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
  83. 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
  84. 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
  85. 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
  86. 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
  87. 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
  88. Leslie, NR, Longy, M. Inherited PTEN mutations and the prediction of phenotype. Semin. Cell Dev. Biol. 2016; 52:30-8. PMID: 26827793
  89. 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
  90. 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
  91. Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 2003; 22(3):183-98. PMID: 12938083
  92. 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
  93. 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
  94. Mester, J, Charis, E. PTEN hamartoma tumor syndrome. Handb Clin Neurol. 2015; 132:129-37. PMID: 26564076
  95. 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
  96. 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
  97. Hearle, N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin. Cancer Res. 2006; 12(10):3209-15. PMID: 16707622
  98. 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
  99. 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
  100. 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
  101. 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
  102. 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
  103. 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
  104. Schneider, K, et al. Li-Fraumeni Syndrome. 1999 Jan 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle. PMID: 20301488
  105. Gonzalez, KD, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J. Med. Genet. 2009; 46(10):689-93. PMID: 19556618
  106. 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
  107. 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
  108. 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
  109. 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
  110. 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
  111. 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
  112. 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
  113. Southey, MC, et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J. Med. Genet. 2016; :None. PMID: 27595995
  114. Helgason, H, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat. Genet. 2015; 47(8):906-10. PMID: 26098866
  115. de, Voer, RM, et al. Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer. Sci Rep. 2015; 5:14060. PMID: 26358404
  116. Baris, HN, et al. Prevalence of breast and colorectal cancer in Ashkenazi Jewish carriers of Fanconi anemia and Bloom syndrome. Isr. Med. Assoc. J. 2007; 9(12):847-50. PMID: 18210922
  117. Cleary, SP, et al. Heterozygosity for the BLM(Ash) mutation and cancer risk. Cancer Res. 2003; 63(8):1769-71. PMID: 12702560
  118. Gruber, SB, et al. BLM heterozygosity and the risk of colorectal cancer. Science. 2002; 297(5589):2013. PMID: 12242432
  119. Nieminen, TT, et al. Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. Gastroenterology. 2014; 147(3):595-598.e5. PMID: 24941021
  120. Seguí, N, et al. GALNT12 is not a major contributor of familial colorectal cancer type X. Hum. Mutat. 2014; 35(1):50-2. PMID: 24115450
  121. Clarke, E, et al. Inherited deleterious variants in GALNT12 are associated with CRC susceptibility. Hum. Mutat. 2012; 33(7):1056-8. PMID: 22461326
  122. Guda, K, et al. Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. Proc. Natl. Acad. Sci. U.S.A. 2009; 106(31):12921-5. doi: 10.1073/pnas.0901454106. PMID: 19617566
  123. Hanks, S, et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet. 2004; 36(11):1159-61. PMID: 15475955
  124. Matsuura, S, et al. Chromosomal instability syndrome of total premature chromatid separation with mosaic variegated aneuploidy is defective in mitotic-spindle checkpoint. Am. J. Hum. Genet. 2000; 67(2):483-6. PMID: 10877982
  125. Rio, Frio, T, et al. Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia. N. Engl. J. Med. 2010; 363(27):2628-37. doi: 10.1056/NEJMoa1006565. PMID: 21190457
  126. Wu, Y, et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat. Genet. 2001; 29(2):137-8. doi: 10.1038/ng1001-137. PMID: 11586295
  127. Liu, HX, et al. The role of hMLH3 in familial colorectal cancer. Cancer Res. 2003; 63(8):1894-9. PMID: 12702580
  128. Sweet, K, et al. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA. 2005; 294(19):2465-73. doi: 10.1001/jama.294.19.2465. PMID: 16287957
  129. Ngeow, J, et al. Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps. Gastroenterology. 2013; 144(7):1402-9, 1409.e1-5. doi: 10.1053/j.gastro.2013.02.001. PMID: 23399955
  130. Nahorski, MS, et al. Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J. Med. Genet. 2010; 47(6):385-90. doi: 10.1136/jmg.2009.073304. PMID: 20522427
  131. Palmirotta, R, et al. Association between Birt Hogg Dube syndrome and cancer predisposition. Anticancer Res. 2010; 30(3):751-7. PMID: 20392993
  132. 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
BLM NM_000057.3
BMPR1A* NM_004329.2
BUB1B NM_001211.5
CDH1 NM_004360.3
CEP57 NM_014679.4
CHEK2 NM_007194.3
ENG NM_000118.3
EPCAM* NM_002354.2
FLCN NM_144997.5
GALNT12 NM_024642.4
GREM1* NM_013372.6
MLH1* NM_000249.3
MLH3 NM_001040108.1
MSH2* NM_000251.2
MSH3 NM_002439.4
MSH6 NM_000179.2
MUTYH NM_001128425.1
NTHL1 NM_002528.6
PMS2 NM_000535.5
POLD1 NM_002691.3
POLE NM_006231.3
PTEN* NM_000314.4
RNF43 NM_017763.5
RPS20 NM_001023.3
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.
GREM1: Analysis of this gene is limited to deletion/duplication analysis of the promoter region.
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.
TP53: Deletion/duplication analysis covers the promoter region.