ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3113A>G (p.Tyr1038Cys) (rs773357672)

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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 RCV000165541 SCV000216273 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000410356 SCV000488823 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-06-24 criteria provided, single submitter clinical testing
GeneDx RCV000483409 SCV000569298 uncertain significance not provided 2018-07-31 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3113A>G at the cDNA level, p.Tyr1038Cys (Y1038C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in a family with a history suspicious for Lynch syndrome (Okkels 2012). MSH6 Tyr1038Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the lever 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 Tyr1038Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000685194 SCV000812667 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1038 of the MSH6 protein (p.Tyr1038Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs773357672, ExAC 0.002%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 22495361). ClinVar contains an entry for this variant (Variation ID: 186021). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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