ClinVar

Description

The c.2005G>T variant (also known as p.G669C), located in coding exon 12 of the MSH2 gene, results from a G to T substitution at nucleotide position 2005. The amino acid change results in glycine to cysteine at codon 669, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in an additional proband whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by IHC (external laboratory communication) and, in a study that quantified tumor characteristics to assess pathogenicity for germline mismatch repair gene variants, this variant was reported in an individual whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression on immunohistochemistry (IHC; Ambry internal data; Li S et al. J. Med. Genet. 2020 Jan;57:62-69). 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 neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.