ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.386C>G (p.Ser129Cys) (rs587779972)

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Total submissions: 6
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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 2019-02-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000587688 SCV000696265 uncertain significance not provided 2015-12-14 criteria provided, single submitter clinical testing
Invitae RCV000629990 SCV000750946 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 129 of the MSH2 protein (p.Ser129Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182577). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000986650 SCV001135701 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Color RCV000492034 SCV001350530 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing

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