ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1321G>A (p.Val441Ile)

gnomAD frequency: 0.00002  dbSNP: rs779701238
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166365 SCV000217154 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-02 criteria provided, single submitter clinical testing The p.V469I variant (also known as c.1405G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1405. The valine at codon 469 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000197060 SCV000254701 uncertain significance Familial adenomatous polyposis 2 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 469 of the MUTYH protein (p.Val469Ile). This variant is present in population databases (rs779701238, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 186723). 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 tolerated. 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 RCV000484811 SCV000567080 uncertain significance not provided 2020-07-27 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health RCV000166365 SCV000685572 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-28 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251492 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.
Counsyl RCV000197060 SCV000790221 uncertain significance Familial adenomatous polyposis 2 2017-03-08 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000166365 SCV002532232 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-18 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV000197060 SCV004828479 uncertain significance Familial adenomatous polyposis 2 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 4/251492 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.

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