Submissions for variant NM_000251.3(MSH2):c.1861C>G (p.Arg621Gly)

dbSNP: rs63750508

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465743	SCV000548260	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 621 of the MSH2 protein (p.Arg621Gly). This variant is present in population databases (rs63750508, gnomAD 0.0009%). This missense change has been observed in individuals with Lynch syndrome (PMID: 23729658; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 408524). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. 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: 30702970; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000483159	SCV000570025	uncertain significance	not provided	2016-04-20	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000561447	SCV000669786	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The p.R621G variant (also known as c.1861C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1861. The arginine at codon 621 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified in several individuals who either met clinical criteria for Lynch syndrome or had clinical features that were consistent with Lynch syndrome, including loss of MSH2 and/or MSH6 by immunohistochemistry (IHC) (Ambry internal data). 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 Jan;108:163-175). Based on an internal structural assessment, this alteration results in local destabilization of a linker loop at the interface between ATPase and lever domains (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192651	SCV001360906	uncertain significance	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1861C>G (p.Arg621Gly) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1861C>G in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classifying the variant as VUS and one calling it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV003449133	SCV004186578	likely pathogenic	Lynch syndrome 1	2023-08-04	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data].