ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1204C>G (p.Gln402Glu)

dbSNP: rs63751412
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255442 SCV000322184 uncertain significance not provided 2023-11-16 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; Published functional studies suggest a neutral effect: demonstrates sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); Observed in individuals with breast cancer (PMID: 28580595); This variant is associated with the following publications: (PMID: 19728162, 18822302, 21120944, 33357406, 28580595, 34284872)
Labcorp Genetics (formerly Invitae), Labcorp RCV000704303 SCV000833247 benign Hereditary nonpolyposis colorectal neoplasms 2023-12-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV001010317 SCV001170494 likely benign Hereditary cancer-predisposing syndrome 2022-11-03 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.
Mendelics RCV002248492 SCV002518262 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV001010317 SCV002528821 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-21 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV003995743 SCV004832590 uncertain significance Lynch syndrome 2023-10-30 criteria provided, single submitter clinical testing This missense variant replaces glutamine with glutamic acid at codon 402 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 MSH2-related disorders in the literature. This variant has been identified in an individual affected with breast cancer (PMID: 28580595). This variant has been identified in 1/251442 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 RCV004567809 SCV005053423 uncertain significance Lynch syndrome 1 2024-03-19 criteria provided, single submitter clinical testing

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