ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.94G>T (p.Gly32Cys) (rs776859837)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198127 SCV000254338 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 32 of the MSH6 protein (p.Gly32Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs776859837, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer and in an individual with pancreatic cancer and family history of ovarian cancer (PMID: 26898890, 28767289). ClinVar contains an entry for this variant (Variation ID: 216325). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000480324 SCV000568988 uncertain significance not provided 2018-01-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.94G>T at the cDNA level, p.Gly32Cys (G32C) at the protein level, and results in the change of a Glycine to a Cysteine (GGC>TGC). This variant has been reported in at least one individual with a personal and family history of breast cancer (Caminsky 2016). MSH6 Gly32Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Gly32Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564851 SCV000662540 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-15 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000663156 SCV000786311 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-04-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480324 SCV000889511 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing
Color RCV000564851 SCV001339378 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing

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