ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1571G>A (p.Arg524His) (rs63751207)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160592 SCV000211187 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1571G>A at the cDNA level, p.Arg524His (R524H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been observed in at least one individual being evaluated for cancer predisposition (Cheng 2017). MSH2 Arg524His 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, Lutzen 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 Arg524His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000218047 SCV000273811 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000228006 SCV000284114 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 524 of the MSH2 protein (p.Arg524His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 182564). 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: 15235030, 17594722, 20672385, 24362816). 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.
Color RCV000218047 SCV000689997 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-04 criteria provided, single submitter clinical testing
Mendelics RCV000708832 SCV000837834 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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