ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.386C>G (p.Ser129Cys)

gnomAD frequency: 0.00001  dbSNP: rs587779972
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587688 SCV000211205 uncertain significance not provided 2018-11-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.386C>G at the cDNA level, p.Ser129Cys (S129C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Ser129Cys was not observed in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Ser129Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000492034 SCV000580516 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-24 criteria provided, single submitter clinical testing The p.S129C variant (also known as c.386C>G), located in coding exon 3 of the MSH2 gene, results from a C to G substitution at nucleotide position 386. The serine at codon 129 is replaced by cysteine, an amino acid with dissimilar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587688 SCV000696265 uncertain significance not provided 2015-12-14 criteria provided, single submitter clinical testing
Invitae RCV000629990 SCV000750946 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-06 criteria provided, single submitter clinical testing
Mendelics RCV000986650 SCV001135701 uncertain significance Lynch syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000492034 SCV001350530 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-30 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 129 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 has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251178 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.
Baylor Genetics RCV000986650 SCV004196270 uncertain significance Lynch syndrome 1 2023-09-06 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003998482 SCV004830144 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 129 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 has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251178 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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