AI Article Synopsis

  • * A patient with suspected Lynch syndrome was found to have a likely de novo mosaic variant (MSH6:c.1135_1139del p.Arg379*), leading to cancers at ages 54 and 58 without any detectable germline variant.
  • * Tumor and blood DNA analysis confirmed the presence of the mosaic variant in normal tissues at low frequencies, suggesting the importance of tumor sequencing and ddPCR in detecting MMR gene mosaicism, which may be key for diagnostics and genetic counseling.

Article Abstract

Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation (MSH6:c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541337PMC
http://dx.doi.org/10.1007/s10689-023-00337-0DOI Listing

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