ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1406A>G (p.Tyr469Cys) (rs748165218)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213108 SCV000275158 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000226561 SCV000283713 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 469 of the MSH6 protein (p.Tyr469Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs748165218, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 231340). 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.
GeneDx RCV000485048 SCV000569035 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1406A>G at the cDNA level, p.Tyr469Cys (Y469C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Tyr469Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Tyr469Cys is located in the mismatch binding 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 Tyr469Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000213108 SCV000690200 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-07 criteria provided, single submitter clinical testing
Mendelics RCV000708866 SCV000837881 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485048 SCV000888237 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing

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