ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.368C>G (p.Ala123Gly)

gnomAD frequency: 0.00002  dbSNP: rs730881767
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212582 SCV000211202 uncertain significance not provided 2022-04-21 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18822302, 21120944)
Ambry Genetics RCV000160606 SCV000215149 likely benign Hereditary cancer-predisposing syndrome 2022-12-06 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 RCV000531566 SCV000625422 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-09-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000160606 SCV000908275 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-11 criteria provided, single submitter clinical testing This missense variant replaces alanine with glycine at codon 123 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250894 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.
All of Us Research Program, National Institutes of Health RCV003998480 SCV004830065 uncertain significance Lynch syndrome 2023-06-28 criteria provided, single submitter clinical testing This missense variant replaces alanine with glycine at codon 123 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250894 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.
Baylor Genetics RCV004567211 SCV005053476 uncertain significance Lynch syndrome 1 2024-01-26 criteria provided, single submitter clinical testing

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