ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1480T>C (p.Ser494Pro)

gnomAD frequency: 0.00001  dbSNP: rs55653533
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219106 SCV000277289 benign Hereditary cancer-predisposing syndrome 2022-04-11 criteria provided, single submitter clinical testing This alteration is classified as 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 RCV000475338 SCV000548287 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-11 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000219106 SCV001344569 likely benign Hereditary cancer-predisposing syndrome 2023-03-08 criteria provided, single submitter clinical testing
GeneDx RCV001589154 SCV001817337 uncertain significance not provided 2023-02-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no impact on mismatch repair function (Jia et al., 2020); Observed in individuals with breast cancer, colon cancer, and/or polyps (Yurgelun et al., 2015; Chang et al., 2016; Chen et al., 2020); This variant is associated with the following publications: (PMID: 26900293, 25980754, 18822302, 9774676, 21120944, 33357406, 32091409)
Sema4, Sema4 RCV000219106 SCV002528849 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-20 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002485427 SCV002779116 uncertain significance Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2 2021-09-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV003462508 SCV004196880 uncertain significance Lynch syndrome 1 2022-12-01 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003998020 SCV004833430 likely benign Lynch syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces serine with proline at codon 494 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 been reported in one individual each affected with colorectal cancer (PMID: 26900293) and Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754), in the latter case the individual also had a pathogenic BRCA1 structural variant. This variant has been identified in 8/282692 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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