ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2875C>T (p.Arg959Cys) (rs751973865)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165958 SCV000216715 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000214010 SCV000279105 uncertain significance not provided 2018-02-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2875C>T at the cDNA level, p.Arg959Cys (R959C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in an individual with a personal and family history of breast and/or ovarian cancer (Caminsky 2016). MSH6 Arg959Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Clamp domain (Warren 2007, 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 MSH6 Arg959Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473325 SCV000551190 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 959 of the MSH6 protein (p.Arg959Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs751973865, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 186374). 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 disruptive, 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.
Color RCV000165958 SCV000685327 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing

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