ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3893A>G (p.Tyr1298Cys) (rs786202520)

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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 RCV000165367 SCV000216093 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000482477 SCV000569813 uncertain significance not provided 2016-04-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3893A>G at the cDNA level, p.Tyr1298Cys (Y1298C) 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 Tyr1298Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Tyr1298Cys occurs at a position that is conserved across species and is located in domain V of the MutS domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Tyr1298Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165367 SCV000690419 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-22 criteria provided, single submitter clinical testing
Invitae RCV000630080 SCV000751036 uncertain significance Hereditary nonpolyposis colon cancer 2018-03-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1298 of the MSH6 protein (p.Tyr1298Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine 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 MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 185867). 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.

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