ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2072T>C (p.Ile691Thr)

dbSNP: rs754824872
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000195748 SCV000254400 benign Hereditary nonpolyposis colorectal neoplasms 2024-11-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000579733 SCV000685007 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-14 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 691 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been reported in individuals affected with Lynch syndrome (PMID: 21671081) and colorectal cancer (PMID: 11606497, 31428572). This variant has been identified in 1/251474 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.
Sema4, Sema4 RCV000579733 SCV002534444 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-21 criteria provided, single submitter curation
GeneDx RCV002307442 SCV002601231 uncertain significance not provided 2022-07-06 criteria provided, single submitter clinical testing Observed in individuals with a personal history of colorectal cancer, with at least some tumors demonstrating microsatellite instability and/or loss of MSH2 protein expression, but all of whom also harbored a second MSH2 variant (Samowitz et al., 2001; Kovac et al., 2011; Zhunussova et al., 2019); 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; This variant is associated with the following publications: (PMID: 31428572, 11606497, 21671081, 18822302, 21120944)
Ambry Genetics RCV000579733 SCV002726347 likely benign Hereditary cancer-predisposing syndrome 2021-10-28 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.
All of Us Research Program, National Institutes of Health RCV003997018 SCV004825283 uncertain significance Lynch syndrome 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 691 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been reported in individuals affected with Lynch syndrome (PMID: 21671081) and colorectal cancer (PMID: 11606497, 31428572). This variant has been identified in 1/251474 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.
Fulgent Genetics, Fulgent Genetics RCV005031746 SCV005661126 uncertain significance Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2 2024-04-16 criteria provided, single submitter clinical testing

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