ClinVar

Description

The p.G761R variant (also known as c.2281G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2281. The glycine at codon 761 is replaced by arginine, an amino acid with dissimilar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 06;218:). The p.G761R variant (c.2281G>C) has been reported in one individual undergoing genetic testing for colorectal cancer predisposition (Rey JM et al. J Mol Diagn, 2017 Jul;19:589-601). This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MSH6 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.