ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1382A>C (p.Asp461Ala)

gnomAD frequency: 0.00003  dbSNP: rs730881756
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160583 SCV000211176 uncertain significance not provided 2021-09-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533, 18822302, 21120944, 9774676)
Invitae RCV000198641 SCV000254384 benign Hereditary nonpolyposis colorectal neoplasms 2024-01-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492025 SCV000580622 likely benign Hereditary cancer-predisposing syndrome 2022-10-03 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.
Color Diagnostics, LLC DBA Color Health RCV000492025 SCV000684934 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-24 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with alanine at codon 461 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250098 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 RCV000662679 SCV000785387 uncertain significance Lynch syndrome 1 2017-07-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160583 SCV000889412 uncertain significance not provided 2019-01-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265636 SCV002547928 uncertain significance not specified 2022-05-09 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000662679 SCV004018321 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.
All of Us Research Program, National Institutes of Health RCV003998470 SCV004833230 uncertain significance Lynch syndrome 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with alanine at codon 461 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250098 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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