ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465743 SCV000548260 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-02 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
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 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-14 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 (Ambry internal data). 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). Based on data from the Genome Aggregation Database (gnomAD), the G allele has an overall frequency of approximately 0.0004% (1/246244) total alleles studied. The highest observed frequency was 0.0009% (1/111696) of Non-Finnish European alleles (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.

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