ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.646A>G (p.Ile216Val)

gnomAD frequency: 0.00002  dbSNP: rs63749936
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216132 SCV000276982 likely benign Hereditary cancer-predisposing syndrome 2016-07-11 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000541467 SCV000625448 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 216 of the MSH2 protein (p.Ile216Val). This variant is present in population databases (rs63749936, gnomAD 0.007%). This missense change has been observed to co-occur in individuals with a different variant in MSH2 that has been determined to be pathogenic (PMID: 11726306; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 91171). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be tolerated (PMID: 22290698). 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 Diagnostics, LLC DBA Color Health RCV000216132 SCV000908281 likely benign Hereditary cancer-predisposing syndrome 2017-06-08 criteria provided, single submitter clinical testing
GeneDx RCV003159097 SCV003852984 uncertain significance not provided 2023-03-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22290698, 11726306, 30212499, 18822302, 21120944)
All of Us Research Program, National Institutes of Health RCV003997179 SCV004830894 likely benign Lynch syndrome 2023-04-27 criteria provided, single submitter clinical testing

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