ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.439G>A (p.Val147Ile)

gnomAD frequency: 0.00001  dbSNP: rs773125415
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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 RCV000458857 SCV000548139 benign Hereditary nonpolyposis colorectal neoplasms 2023-10-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568213 SCV000669750 likely benign Hereditary cancer-predisposing syndrome 2023-11-20 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759835 SCV000889440 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000568213 SCV000903295 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-19 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 147 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 reported in an individual affected with ovarian cancer (PMID: 33357406). This variant has been identified in 3/251448 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.
GeneDx RCV000759835 SCV004170482 uncertain significance not provided 2023-10-18 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; Observed in an individual with high-grade serous carcinoma in published literature (Andrikopoulou et al., 2022); Published functional studies suggest a neutral effect: demonstrates sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (Jia et al., 2020); This variant is associated with the following publications: (PMID: 18822302, 21120944, 36531003, 33357406)
Myriad Genetics, Inc. RCV003449128 SCV004186070 likely benign Lynch syndrome 1 2023-11-22 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
All of Us Research Program, National Institutes of Health RCV004000775 SCV004830288 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 147 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 reported in an individual affected with ovarian cancer (PMID: 33357406). This variant has been identified in 3/251448 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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