ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 669 of the MSH2 protein (p.Gly669Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 90852). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 18383312, 22290698). Experimental studies have shown that this missense change affects MSH2 function (PMID: 23690608, 28422960). This variant disrupts the c.2006G>T nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10612827, 21520333, 26247049, 27629256; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.G669D variant (also known as c.2006G>A) is located in coding exon 13 of the MSH2 gene. The glycine at codon 669 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 13. This alteration, p.G669D, was identified in a HNPCC family and the colon tumor of the proband displayed high microsatellite instability (MSI-H) with loss of both MSH2/MSH6 expression on immunohistochemistry (IHC) (Losi L et al. Am. J. Gastroenterol., 2005 Oct;100:2280-7; de Leon MP et al. Scand. J. Gastroenterol., 2007 Jun;42:746-53; Pedroni M et al. Dis. Markers, 2007;23:179-87). This alteration was also identified as somatic in origin in conjunction with a somatic pathogenic mutation in MSH2 in a colorectal tumor that displayed loss of both MSH2/MSH6 on IHC (Ambry internal data). This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). In one functional study, this variant demonstrated a high mutation rate as well as severely reduced protein expression in mutagen treated murine ES cells and mismatch repair activity was reduced (~10%) compared to wild type MSH2 (100%) in an in vitro complementation assay (Drost M et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Jun;110:9403-8). Based on an internal structural assessment, this alteration disrupts the ATP-binding P-loop motif (Saraste M et al. Trends Biochem. Sci., 1990 Nov;15:430-4; Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant was not reported in population-based 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.

MSH2 NM_000251.2:c.2006G>A has a 93.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23690608]. This variant is expected to disrupt protein structure [Myriad internal data].