ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.631G>A (p.Gly211Arg) (rs587780689)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122991 SCV000166284 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 211 of the MSH2 protein (p.Gly211Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 135863). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000222170 SCV000274682 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000486574 SCV000566428 uncertain significance not provided 2016-04-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.631G>A at the cDNA level, p.Gly211Arg (G211R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gly211Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly211Arg occurs at a position that is not conserved and is located within the Connector domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Gly211Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.

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