ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.476C>T (p.Ala159Val) (rs587778528)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215694 SCV000275393 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215694 SCV000911113 likely benign Hereditary cancer-predisposing syndrome 2017-02-09 criteria provided, single submitter clinical testing
ITMI RCV000121571 SCV000085767 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000586380 SCV000695915 uncertain significance not provided 2016-05-03 criteria provided, single submitter clinical testing Variant summary: The c.476C>T variant affects a conserved nucleotide, resulting in amino acid change from Ala to Val. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 4/120712 control chromosomes at a frequency of 0.0000331, which does not exceed maximal expected frequency of a pathogenic allele (0.0001421). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000457237 SCV000551076 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 159 of the MSH6 protein (p.Ala159Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs587778528, ExAC 0.005%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 134848). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0") 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 and its clinical significance is uncertain. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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