Identifying Patients with Lynch Syndrome: A Paired Somatic/Germline Testing Approach

Lynch syndrome is one of the most common hereditary cancer syndromes, affecting about 1/279-1/440 people in the U.S. It is caused by a genetic mutation in one of five genes: MLH1, MSH2, MSH6, PMS2, or EPCAM. Individuals with Lynch syndrome have a significantly increased lifetime risk for multiple types of cancer including colorectal (up to 82% lifetime risk), uterine (up to 60% lifetime risk), stomach, ovarian, and others. It is critical to identify people with this condition, so that clinicians can make personalized medical management recommendations to increase early detection and prevention. Additionally, if an individual is known to have Lynch syndrome, then their family members may also be at-risk and could benefit from genetic testing.

Given the incidence rate of Lynch syndrome and the importance of identifying those with this condition, many hospitals have implemented universal screening programs. While the programs can vary between hospitals, they often call for all newly diagnosed colorectal or uterine cancers to undergo tumor screening via microsatellite instability analysis (MSI) and/or immunohistochemistry (IHC) of the mismatch repair proteins.  If the results of MSI or IHC screening are abnormal, this may be suggestive of Lynch syndrome. Additionally, individuals with abnormal MSI or IHC are said to have “mismatch repair deficient” tumors, and thus may be eligible for additional treatment options.

When someone has abnormal tumor screening results, several additional steps can be taken to further clarify whether or not the individual actually has Lynch syndrome, including germline genetic testing. However, for a significant portion of suspected Lynch syndrome cases (up to 64% colorectal and up to 62% endometrial), the result of germline genetic testing is discordant with the result of the tumor screening.1 In other words, the tumor screening was abnormal, but the germline testing was normal. This situation can cause a clinical dilemma for healthcare providers, since it makes the diagnosis of Lynch syndrome unclear, and makes it difficult to counsel the patient and their family members regarding future cancer risks and medical management. 

Studies have shown that up to 70% of discordant cases can be explained by 2 somatic (isolated to the tumor) mutations in a Lynch syndrome gene2. For individuals known to have 2 somatic mutations, the likelihood of Lynch syndrome is significantly reduced and management recommendations may become clearer. Therefore, a paired tumor/germline testing approach can reduce the likelihood of discordant results and provide the information necessary to rule out or confirm a diagnosis of Lynch syndrome with one test.

Learn more about Ambry’s paired somatic/germline testing, TumorNext-Lynch, and how it can bring more clarity to your patients by attending our upcoming webinar, or visting the test page on our website.


  1. Buchanan et al. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet. 2014. 7:183-93.
  2. Haraldsdottir et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014. 147(6):1308-1316.

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