ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.394G>A (p.Val132Ile) (rs763273196)

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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 RCV000165052 SCV000215753 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-07 criteria provided, single submitter clinical testing The p.V132I variant (also known as c.394G>A), located in coding exon 5 of the MUTYH gene, results from a G to A substitution at nucleotide position 394. The valine at codon 132 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000466109 SCV000545738 uncertain significance MYH-associated polyposis 2020-04-19 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 132 of the MUTYH protein (p.Val132Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs763273196, ExAC 0.001%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 185604). 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.
Color Health, Inc RCV000165052 SCV000685626 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251414 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590403 SCV000697695 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.394G>A (p.Val132Ile) variant located in the DNA glycosylase domain (via InterPro) involves the alteration of a conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121382, which does not exceed the estimated maximal expected allele frequency for a pathogenic MUTYH variant of 1/219. The variant of interest has not been, to our knowledge, reported in affected individuals via publications, although a clinical diagnostic laboratory cites the variant with a classification of "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590403 SCV001134477 uncertain significance not provided 2019-07-23 criteria provided, single submitter clinical testing

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