ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.701C>T (p.Thr234Ile)

gnomAD frequency: 0.00001  dbSNP: rs730881773
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160625 SCV000211224 uncertain significance not provided 2023-02-13 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; Observed in an individual with breast cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 18822302, 21120944, 25186627)
Labcorp Genetics (formerly Invitae), Labcorp RCV000473583 SCV000548175 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562874 SCV000669832 likely benign Hereditary cancer-predisposing syndrome 2023-04-27 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.
Color Diagnostics, LLC DBA Color Health RCV000562874 SCV000685120 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-24 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 234 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has also been identified in 2/251348 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.
Counsyl RCV000663301 SCV000786554 uncertain significance Lynch syndrome 1 2018-05-22 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000663301 SCV004018317 uncertain significance Lynch syndrome 1 2023-03-20 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV000663301 SCV004196248 uncertain significance Lynch syndrome 1 2024-03-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160625 SCV004221013 uncertain significance not provided 2023-06-06 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an individual affected with breast cancer (PMID: 25186627 (2015)). The results from one indirect functional study indicated that the variant likely retains DNA mismatch repair activity (PMID: 33357406 (2021)), however, further research is needed. The frequency of this variant in the general population, 0.000008 (2/251348 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 RCV004806115 SCV005429058 uncertain significance Lynch syndrome 2024-03-28 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 234 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has also been identified in 2/251348 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV005359370 SCV005921154 uncertain significance Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2 2024-06-04 criteria provided, single submitter clinical testing

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