Ordering
  • Test code: 01252
  • 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
 

Invitae Colorectal Cancer Guidelines-Based Panel

Test description

The Invitae Colorectal Cancer Guidelines-Based Panel analyzes up to 20 genes associated with a significantly elevated risk of hereditary colorectal cancer. These genes were curated based on published best practice guidelines for evaluation of hereditary colorectal cancer (CRC) risk. The genes included in this panel are medically actionable and have published, evidence-based management and risk-reduction options.

Individuals with hereditary cancer risk have an elevated chance of developing cancer and require specialized—often intensive—management. This test will help guide cancer screening and risk-reduction measures for colorectal cancer, including defining the age at which screening is initiated, the interval between screening tests, the methodology used, preventive options including surgery, and the risk for subsequent primary cancers. These measures may prevent cancer or lead to earlier diagnosis, increasing the chances of successful treatment and survival.

PTEN: Deletion/duplication analysis covers the promoter region.

Order test

Primary panel (19 genes)

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

Add-on Gene with Emerging Data for Colorectal Cancer (1 gene)

Invitae offers this gene as an add-on to our guidelines-based colorectal panel based on recent clinical updates.

RPS20

Alternative tests to consider

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

  • Lynch syndrome (LS)
  • familial adenomatous polyposis (FAP)
  • attenuated familial adenomatous polyposis (AFAP)
  • MUTYH-associated polyposis (MAP)
  • Peutz-Jeghers syndrome (PJS)
  • juvenile polyposis syndrome (JPS)
  • serrated polyposis syndrome (SPS)
  • Li-Fraumeni syndrome (LFS)
  • Cowden and Cowden-like syndrome (CS)
  • oligodontia-colorectal cancer syndrome
  • constitutional mismatch repair deficiency (CMMR-D)

Colorectal cancer (CRC) is a malignancy of the large intestine (colon) 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 EPCAM, MLH1, MSH2, MSH6, and PMS2. This condition is the most common inherited cause of colorectal cancer. Polyposis syndromes are characterized by the development of numerous precancerous polyps that 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 colorectal cancer 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, the Invitae Colorectal Cancer Guidelines-Based Panel tests for other hereditary colorectal cancer syndromes, most 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 cancer, and many of these cancers may be difficult to detect 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, see the table below.

GeneColorectal cancer riskOther associated cancers
APC 70%–100%  (PMID: 18063416, 19822006, 1673441) sarcoma, duodenal, brain, thyroid, hepatoblastoma, upper stomach
AXIN2 elevated (PMID: 21416598, 26025668, 15042511, 23838596)
BMPR1A 38%–68% (PMID: 25645574, 16246179, 17303595) gastric, pancreatic
CHEK2 elevated (PMID: 21807500, 23713947, 23946381, 17164383) breast, thyroid, prostate
EPCAM 75%–82% (PMID: 21145788, 20301390) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
GREM1 elevated (PMID: 26169059, 22561515, 25419707)
MLH1 up to 82% (PMID: 20301390, 25070057) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
MSH2 up to 82% (PMID: 20301390, 25070057) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
MSH3 elevated (PMID: 27476653)
MSH6 ♂: up to 44% ♀: up to 20% (PMID: 20028993) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
MUTYH 43%–100% (PMID: 23035301, 19620482) duodenal
NTHL1 elevated (PMID: 25938944, 26559593, 26431160, 27720914, 17029639)
PMS2 up to 20% (PMID: 18602922) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
POLD1 elevated (PMID: 23263490, 26133394, 25529843)
POLE elevated (PMID: 23263490, 26133394, 25529843)
PTEN 9% (PMID: 22252256) breast, uterine, renal, thyroid, brain, skin
SMAD4 38%–68% (PMID: 25645574, 16246179, 17303595) gastric, pancreatic
STK11 39% (PMID: 20051941) breast, ovarian, uterine, gastric, pancreatic, duodenal, lung
TP53 elevated (PMID: 16401470) breast, ovarian, uterine, gastric, pancreatic, sarcoma, brain, lung, adrenal, leukemia

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

Colorectal cancer occurs in approximately 1 in 22 individuals in the general population. Up to 5% of all colon cancer cases are attributed to Lynch syndrome.

APC-associated polyposis conditions historically accounted for approximately 0.5% of all colon cancer, but this number is decreasing with greater awareness, early detection, and intervention. Collectively, the APC-associated polyposis conditions have a prevalence of approximately 2-3 in 100,000 individuals.

Approximately 1%-2% of individuals of northern European ancestry are carriers of a MUTYH variant. The prevalence of MAP in this population is estimated at 1 in 20,000 to 1 in 40,000. It is difficult to determine the prevalence of this condition in other ethnicities because the carrier frequency can vary significantly.

Practice guidelines assist in identifying individuals who may benefit from consideration of this test, including those with a personal or family history of:

  • colorectal or endometrial cancer diagnosed before age 50
  • multiple primary colorectal tumors
  • tumors of the colorectum, uterus, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, sebaceous glands, and keratoacanthomas in three or more relatives
  • greater than 10 colorectal adenomas
  • desmoid tumors, cribriform morular variant of papillary thyroid cancer, multiple extraintestinal gastrointestinal adenomas, or hepatoblastoma
  • gastrointestinal ganglioneuromas or polyps of the hamartomatous, juvenile, ganglio, or serrated type
  • abnormal tumor pathology suggestive of a mismatch repair defect (MSI, IHC, Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern)

  1. Cybulski, C, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet. 2004; 75(6):1131-5. PMID: 15492928
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. Xiang, HP, et al. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur. J. Cancer. 2011; 47(17):2546-51. PMID: 21807500
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. Leslie, NR, Longy, M. Inherited PTEN mutations and the prediction of phenotype. Semin. Cell Dev. Biol. 2016; 52:30-8. PMID: 26827793
  35. 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
  36. 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
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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
  42. Bisgaard, ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat. 1994; 3(2):121-5. PMID: 8199592
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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
  52. 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
  53. 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
  54. 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
  55. Hearle, N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin. Cancer Res. 2006; 12(10):3209-15. PMID: 16707622
  56. 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
  57. 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
  58. Kuiper, RP, Hoogerbrugge, N. NTHL1 defines novel cancer syndrome. Oncotarget. 2015; 6(33):34069-70. PMID: 26431160
  59. Belhadj, S, et al. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis. Clin. Gastroenterol. Hepatol. 2017; 15(3):461-462. PMID: 27720914
  60. 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
  61. 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
  62. 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
  63. Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 2003; 22(3):183-98. PMID: 12938083
  64. 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
  65. Mester, J, Charis, E. PTEN hamartoma tumor syndrome. Handb Clin Neurol. 2015; 132:129-37. PMID: 26564076
  66. 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
  67. Gonzalez, KD, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J. Med. Genet. 2009; 46(10):689-93. PMID: 19556618
  68. 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
  69. 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
  70. 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
  71. 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
  72. 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
  73. 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
  74. 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
  75. 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
  76. 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
  77. 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
  78. 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
  79. 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
  80. 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
  81. 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
  82. Aarnio, M. Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012; 2012:350309. doi: 10.1155/2012/350309. PMID: 22619739
  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. 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
  85. 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
  86. 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
  87. 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
  88. 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
  89. 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
  90. 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
  91. 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
  92. 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
  93. 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
  94. Half, E, et al. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009; 4:22. doi: 10.1186/1750-1172-4-22. PMID: 19822006
  95. Neklason, DW, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(1):46-52. PMID: 18063416
  96. 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
  97. Schneider, K, et al. Li-Fraumeni Syndrome. 1999 Jan 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle. PMID: 20301488
  98. 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
  99. 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
  100. 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
  101. 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
  102. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  103. 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.

For management recommendations, please refer to:

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, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. 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
AXIN2 NM_004655.3
BMPR1A* NM_004329.2
CHEK2 NM_007194.3
EPCAM* NM_002354.2
GREM1* NM_013372.6
MLH1* NM_000249.3
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
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. Sequencing analysis for exons 5 includes only cds +/- 10 bp.
BMPR1A: Deletion/duplication analysis covers the promoter region.
EPCAM: Sequencing analysis is not offered for this gene.
GREM1: Promoter region duplication testing only.
MLH1: Deletion/duplication analysis covers the promoter region. Sequencing analysis for exons 12 includes only cds +/- 10 bp.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation). Sequencing analysis for exons 2, 5 includes only cds +/- 10 bp.
MSH3: Sequencing analysis of the repeat region of exon 1 (5:79950697-79950765) is not offered
MSH6: Sequencing analysis for exons 7, 10 includes only cds +/- 10 bp.
PMS2: Sequencing analysis for exons 7 includes only cds +/- 10 bp.
POLD1: Sequencing analysis for exons 22 includes only cds +/- 10 bp.
PTEN: Deletion/duplication analysis covers the promoter region. Sequencing analysis for exons 8 includes only cds +/- 10 bp.
TP53: Deletion/duplication analysis covers the promoter region.