ClinVar

Description

Variant summary: MSH2 c.126C>G (p.Phe42Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229070 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.126C>G has been reported in the literature as a VUS in settings of multigene panel testing in at-least one female with breast cancer after the age of 50 who had a low risk based on family history and was referred for commercial BRCA1/2 testing (example, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.