ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2038C>G (p.Arg680Gly) (rs63749932)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165747 SCV000216490 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000589676 SCV000566955 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2038C>G at the cDNA level, p.Arg680Gly (R680G) 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 Arg680Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Arg680Gly is located in the ATPase domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Arg680Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589676 SCV000696232 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2038C>G (p.Arg680Gly) variant located in the DNA mismatch repair protein MutS, core domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. However, these predictions have yet to be functionally assessed.. This variant was found in 2/121304 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000693732 SCV000821613 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 680 of the MSH2 protein (p.Arg680Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs63749932, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 186199). 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. 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.

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