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Lynch syndrome confers an increased risk to various types of cancer, in particular early onset colorectal and endometrial cancer. Mutations in mismatch repair (MMR) genes underlie Lynch syndrome, with the majority of mutations found in  MLH1  and  MSH2 . Mutations in  MSH6  have also been found but these do not always cause a clear cancer predisposition phenotype and  MSH6 -defective tumors often do not show the standard characteristics of MMR deficiency, such as microsatellite instability. In particular, the consequences of  MSH6  missense mutations are challenging to predict, which further complicates genetic counseling. We have previously developed a method for functional characterization of  MSH2  missense mutations of unknown significance. This method is based on endogenous gene modification in mouse embryonic stem cells using oligonucleotide-directed gene targeting, followed by a series of functional assays addressing the MMR functions. Here we have adapted this method for the characterization of  MSH6  missense mutations. We recreated three  MSH6  variants found in suspected Lynch syndrome families, MSH6-P1087R, MSH6-R1095H and MSH6-L1354Q, and found all three to behave like wild type MSH6. Thus, despite suspicion for pathogenicity from clinical observations, our approach indicates these variants are not disease causing. This has important implications for counseling of mutation carriers.

Functional Analysis in Mouse Embryonic Stem Cells Reveals Wild-Type Activity for Three Msh6 Variants Found in Suspected Lynch Syndrome Patients