ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.242C>T (p.Ala81Val) (rs587779924)

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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 RCV000115391 SCV000214975 likely benign Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000115391 SCV000910869 benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Counsyl RCV000412014 SCV000487971 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000588221 SCV000149300 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.242C>T at the cDNA level, p.Ala81Val (A81V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has been observed in an individual with ovarian cancer and another individual with colon cancer which was MSI stable (Pal 2012, Hampel 2018). MSH6 Ala81Val was not observed 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 Ala81Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588221 SCV000695810 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing Variant summary: The c.242C>T (p.Ala81Val) in MSH6 gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain. The variant is absent from control dataset of ExAC. This variant has been reported in affected individual developed OvC, but is cited as VUS/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more information becomes available.
Invitae RCV000477204 SCV000551136 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 81 of the MSH6 protein (p.Ala81Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. While this variant is not present in population databases (rs587779924), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 127571). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, these predictions have not been confirmed by published functional 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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