ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1570C>T (p.Arg524Cys) (rs755818010)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759820 SCV000570933 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1570C>T at the cDNA level, p.Arg524Cys (R524C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in an individual with thyroid cancer (Yehia 2018). MSH2 Arg524Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the clamp domain as well as the region of interaction with MSH6 and MSH3 (Guerrette 1998, 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 Arg524Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000484414 SCV000595832 uncertain significance not specified 2016-12-16 criteria provided, single submitter clinical testing
Invitae RCV000552575 SCV000625285 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 524 of the MSH2 protein (p.Arg524Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs755818010, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 421654). 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. A different missense substitution at this codon (p.Arg524Pro) has been determined to be pathogenic (PMID: 10469597, 7937795, 17594722, 206672385, 7937795, 15849733, 18931482, 26845104). This suggests that the arginine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. 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 RCV000569307 SCV000662240 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Well-characterized mutation at same position
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759820 SCV000889415 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001250041 SCV001423966 uncertain significance Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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