ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1270C>T (p.His424Tyr)

gnomAD frequency: 0.00001  dbSNP: rs587782278
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131137 SCV000186072 likely benign Hereditary cancer-predisposing syndrome 2018-12-06 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000464371 SCV000548214 benign Hereditary nonpolyposis colorectal neoplasms 2023-12-12 criteria provided, single submitter clinical testing
GeneDx RCV000481281 SCV000565728 uncertain significance not provided 2023-02-03 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; Observed in an individual with ovarian cancer (Pal et al., 2012); This variant is associated with the following publications: (PMID: 28944238, 21120944, 18822302, 23047549)
Color Diagnostics, LLC DBA Color Health RCV000131137 SCV000689968 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-26 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 424 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with epithelial ovarian cancer (PMID: 23047549). This variant has been identified in 3/251198 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genetics and Molecular Pathology, SA Pathology RCV003447501 SCV004175369 uncertain significance Lynch syndrome 1 2020-09-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481281 SCV004220942 uncertain significance not provided 2023-08-23 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)), and also in an unaffected control individual in a colorectal cancer study (PMID: 28944238 (2017)). The frequency of this variant in the general population, 0.000071 (3/42072 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health RCV003998086 SCV004832724 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 424 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with epithelial ovarian cancer (PMID: 23047549). This variant has been identified in 3/251198 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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