ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1528A>T (p.Met510Leu) (rs587780080)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212722 SCV000149660 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1570A>T at the cDNA level, p.Met524Leu (M524L) at the protein level, and results in the change of a Methionine to a Leucine (ATG>TTG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MUTYH Met524Leu was not observed in large population cohorts (Lek 2016). This variant is located within the PCNA binding domain (Ruggieri 2013). 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 MUTYH Met524Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Ambry Genetics RCV000115751 SCV000185768 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing The p.M524L variant (also known as c.1570A>T), located in coding exon 16 of the MUTYH gene, results from an A to T substitution at nucleotide position 1570. The methionine at codon 524 is replaced by leucine, 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.
Invitae RCV000233496 SCV000285939 uncertain significance MYH-associated polyposis 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 524 of the MUTYH protein (p.Met524Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 127833). 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 leucine 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.
Counsyl RCV000233496 SCV000790110 uncertain significance MYH-associated polyposis 2017-03-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115751 SCV000905849 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This missense variant replaces methionine with leucine at codon 524 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 not been identified 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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