ClinVar

Description

Variant summary: MSH6 c.3758T>C (p.Val1253Ala) results in a non-conservative amino acid change in 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 1.6e-05 in 251190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3758T>C has been reported in the literature in individuals affected with Colorectal Cancer, Hereditary Breast Cancer, or suspected Lynch syndrome without evidence for causality, often reported as a VUS (Chubb_2015, Yurgelun_2015, Dudley_2018, Pearlman_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25559809, 29360161, 34250417). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.