RNA Genetic Testing Brings Clarity to Lynch Syndrome Patients


MSH2 is one of five genes associated with Lynch syndrome, a condition that leaves patients with a significantly increased risk for colorectal and certain other cancers. Using genetic testing to identify patients with Lynch syndrome is important because they can be recommended increased cancer screenings for early detection and prevention.

MSH2, specifically, has the highest number of germline duplications of any Lynch syndrome gene1. Why is this problematic? Duplications are most often classified as variants of unknown significance (VUS) because looking at the DNA alone cannot tell us the location of a duplication. This information is important because it can tell us if the duplication is located adjacent to the gene (in-tandem), thereby disrupting gene function, or if it is located somewhere else in the genome.

All variants identified in a genetic test are classified using multiple lines of evidence according to the guidelines set out by the American College of Medical Genetics and Genomics (ACMG), and the classification of a variant signifies its role in a disease2. When a variant is ultimately classified as VUS, however, clinicians are often not able to make clear recommendations.

In our recent publication in Gastroenterology, we have identified 5 patients with different MSH2 exonic duplications from >185,000 individuals that underwent DNA genetic testing at Ambry Genetics3. These patients received additional RNA genetic testing that provided evidence that the duplications occur in-tandem and disrupt the function of the gene. This functional evidence is weighted highly in the ACMG classification scheme, and ultimately enabled reclassification from VUS to clinically actionable pathogenic variants.

Reclassification of these MSH2 exonic duplications allows us to provide clear results enabling healthcare providers to diagnose their patients with Lynch syndrome personalize cancer risk counseling and tailor management recommendations4. These results are also important for family members of the patient who can now be tested to determine if they have Lynch syndrome.

RNA genetic testing has the potential to clarify the significance of germline exonic duplications, bringing clarity to genetic testing results by reducing the number of VUS. This approach can also be applied to other types of variants that may impact RNA splicing and/or expression, helping to clarify VUS results for more patients and families.  

Read the complete study for more information.


  1. Mu W, et al. Genet Med 2018; doi: 10.1038/s41436-018-0397-6.
  2. Richards S, et al. Genet Med 2015;17:405-24.
  3. Conner BR, et al. Gastroenterology 2019; doi:10.1053/j.gastro.2019.01.248.
  4. NCCN Clinical Practice Guidelines in Oncology. V.3.2017 ed.

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The information, including but not limited to, text, graphics, images and other material contained on this blog are for informational purposes only. The purpose of this blog is to promote broad understanding and knowledge of various health topics. It is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this blog. Ambry Genetics Corporation does not recommend or endorse any specific tests, physicians, products, procedures, opinions or other information that may be mentioned on this blog. Reliance on any information appearing on this blog is solely at your own risk.


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