ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1205C>T (p.Pro402Leu) (rs587780079)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212716 SCV000149659 uncertain significance not provided 2018-02-22 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1289C>T at the cDNA level, p.Pro430Leu (P430L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Pro430Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Nudix hydrolase domain (Ruggieri 2013, UniProt). 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 Pro430Leu 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 MUTYH pathogenic variants on opposite chromosomes.
Ambry Genetics RCV000115750 SCV000217731 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-27 criteria provided, single submitter clinical testing The p.P430L variant (also known as c.1289C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1289. The proline at codon 430 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available higher 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 RCV000471700 SCV000545730 uncertain significance MYH-associated polyposis 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 430 of the MUTYH protein (p.Pro430Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline 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: 127832). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". 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.
Color Health, Inc RCV000115750 SCV000690513 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-28 criteria provided, single submitter clinical testing
Mendelics RCV000471700 SCV000837747 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing

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