ClinVar

Description

This variant is denoted MSH2 c.1861C>G at the cDNA level, p.Arg621Gly (R621G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Arg621Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Arg621Gly occurs at a position that is conserved across species and is located in the ATPase domain and region of interaction with EXO1 (Lutzen 2008) . Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function while multiple splicing models predict that this variant may create a weak cryptic splice acceptor site upstream of the unaffected natural splice acceptor site in exon 12. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH2 Arg621Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.