ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1498G>A (p.Ala500Thr) (rs786204127)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168089 SCV000218743 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 500 of the MSH6 protein (p.Ala500Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. 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: 188181). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000657123 SCV000279936 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1498G>A at the cDNA level, p.Ala500Thr (A500T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala500Thr was not observed at a significant frequency in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ala500Thr is located within the mismatch binding domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Ala500Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657123 SCV000601508 uncertain significance not provided 2019-03-27 criteria provided, single submitter clinical testing
GeneID Lab - Advanced Molecular Diagnostics RCV000578381 SCV000680453 uncertain significance Lynch syndrome 2017-09-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV001011904 SCV001172286 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001011904 SCV001346916 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-08 criteria provided, single submitter clinical testing

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