ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1861C>G (p.Arg621Gly) (rs63750508)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561447 SCV000669786 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Structural Evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
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.
Invitae RCV000465743 SCV000548260 uncertain significance Lynch syndrome 2016-07-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 621 of the MSH2 protein (p.Arg621Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs63750508, ExAC 0.001%). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and in an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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