ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 621 of the MSH2 protein (p.Arg621Gln). This variant is present in population databases (rs759263820, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141). ClinVar contains an entry for this variant (Variation ID: 455528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg621 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21520333, 30702970; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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.