ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.163C>G (p.Arg55Gly)

gnomAD frequency: 0.00001  dbSNP: rs587782354
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131300 SCV000186272 likely benign Hereditary cancer-predisposing syndrome 2023-06-14 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.
GeneDx RCV000212579 SCV000211240 uncertain significance not provided 2019-11-25 criteria provided, single submitter clinical testing Observed in an individual with cancer, type not specified (Li 2019); Published functional studies demonstrate reduced or absent MSH2 mRNA and protein expression in transfected cell lines (Arora 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31391288, 28494185)
Invitae RCV000545235 SCV000625289 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131300 SCV000684957 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 55 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). In another functional study, this variant causes decreased mRNA and protein expression as well as a reduced DNA damage response compared to wild type (PMID: 28494185). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 4/264300 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.
All of Us Research Program, National Institutes of Health RCV003998100 SCV004831916 uncertain significance Lynch syndrome 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 55 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). In another functional study, this variant causes decreased mRNA and protein expression as well as a reduced DNA damage response compared to wild type (PMID: 28494185). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 4/264300 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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