• Test code: 01702
  • 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

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)

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 – also known as hereditary non-polyposis colorectal cancer (HNPCC)
  • congenital tufting enteropathy
  • constitutional mismatch repair deficiency (CMMR-D) syndrome

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. 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
  2. Senter, L, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008; 135(2):419-28. PMID: 18602922
  3. 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
  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. 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
  7. 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
  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. 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
  10. 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
  11. 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
  12. 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
  13. Goodenberger, ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.27. PMID: 25856668
  14. 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.
  15. 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
  16. Aarnio, M. Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012; 2012:350309. doi: 10.1155/2012/350309. PMID: 22619739
  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 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
EPCAM* NM_002354.2
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH6* NM_000179.2
PMS2* NM_000535.5

EPCAM: Sequencing analysis is not offered for this gene.
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.
MSH6: Sequencing analysis for exons 7, 10 includes only cds +/- 10 bp.
PMS2: Sequencing analysis for exons 7 includes only cds +/- 10 bp.