Invitae Lynch Syndrome Panel


Test description

This test analyzes 5 genes associated with a hereditary predisposition to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer [HNPCC]). This tumor predisposition syndrome is characterized by an increased risk of developing colorectal, ovarian, uterine, and other cancers.

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 (5 genes)


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).

Alternative tests to consider

MLH1, MSH2, PMS2, MSH6, and EPCAM can also be ordered as part of a broader panel to test for different types of hereditary cancer, including ovarian, uterine, colon, and pancreatic cancers. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.

Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]), constitutional mismatch repair deficiency (CMMR-D) syndrome, congenital tufting enteropathy

Lynch syndrome, also called hereditary non-polyposis colon cancer (HNPCC), increases the risk of many types of cancer, particularly colorectal. Other associated cancers include stomach, small bowel, kidney, central nervous system, biliary tract, pancreatic, prostate and skin. Women with this disorder also have an increased risk for ovarian and uterine cancer. Lynch syndrome is the most common cause of adult-onset hereditary colorectal and uterine cancers.

Colorectal cancer (CRC) is a malignancy of the large intestine (colon) and/or rectum. It is the third-commonest cancer diagnosis in the United States. Although most cases are sporadic and not inherited, approximately 5%-10% of colorectal cancer is hereditary and due to an identifiable pathogenic variant. Up to 5% of all colorectal cancer cases are attributed to Lynch syndrome.

Individuals with Lynch syndrome due to a pathogenic variant in MLH1, MSH2, PMS2, or MSH6 are also carriers of constitutional mismatch-repair deficiency (CMMR-D) syndrome.

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 can present differently, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant. See table below for gene-associated cancer risks.

GeneColorectal cancer riskOvarian cancer riskUterine cancer riskOther associated cancers
MLH1 Up to 82% Up to 20% 14%-54% GI, urothelial/renal, CNS, biliary tract, glioblastoma, and sebaceous adenoma/carcinoma
MSH2 Up to 82% up to 24% 20%-54%
MSH6 20%-44% 6%-8% Up to 71%
PMS2 Up to 20% Elevated Up to 15%
EPCAM 75%-82% Elevated 12%-55%

Approximately 5%-10% of colorectal cancer is hereditary and due to an identifiable pathogenic variant. Up to 5% of all colorectal cancer cases are attributed to pathogenic mutations in one of the genes associated with Lynch syndrome.

GenePercentage of Lynch syndrome cases attributed to each gene
MLH1 50%
MSH2 40%
MSH6 7%-10%
PMS2 <5%
EPCAM 1%-3%

Lynch syndrome is inherited in an autosomal dominant pattern.

Individuals who meet the Amsterdam II Criteria have an established diagnosis of Lynch syndrome, although many affected individuals do not meet these guidelines:

  • at least 3 relatives with a Lynch-related cancer
  • one relative is a first-degree relative of the other two
  • Lynch-related cancers in at least two successive generations
  • at least one Lynch-related cancer diagnosed under age 50
  • familial adenomatous polyposis (FAP) ruled out in colon cancer cases

Criteria for evaluating individuals for Lynch syndrome have been established by the National Comprehensive Cancer Network:

The Revised Bethesda Guidelines may also be used to screen individuals with colon cancer for Lynch syndrome:

  1. Aarnio, M. Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012; 2012:350309. doi: 10.1155/2012/350309. PMID: 22619739
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  8. Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
  9. Hegde, MR, Roa, BB. Genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC). Curr Protoc Hum Genet. 2009; Chapter 10:Unit 10.12. doi: 10.1002/0471142905.hg1012s61. PMID: 19360696
  10. 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. doi: 10.1053/j.gastro.2004.03.068. PMID: 15236168
  11. Kang, SY, et al. Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers. Int. J. Cancer. 2015; 136(7):1568-78. doi: 10.1002/ijc.29133. PMID: 25110875
  12. 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
  13. Kohlmann, W, Gruber, SB. Lynch Syndrome. 2004 Feb 05. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301390
  14. National Comprehensive Cancer Network, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Colorectal. Accessed September 2015.
  15. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  16. Umar, A, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 2004; 96(4):261-8. doi: 10.1093/jnci/djh281. PMID: 14970275
  17. Vasen, HF, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999; 116(6):1453-6. PMID: 10348829

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
EPCAM* NM_002354.2
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH6 NM_000179.2
PMS2 NM_000535.5

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).