ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.548G>A (p.Gly183Asp) (rs587781864)

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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 RCV000130180 SCV000185017 pathogenic Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000130180 SCV000690583 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503917 SCV000592687 uncertain significance not specified 2013-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000519177 SCV000619213 likely pathogenic not provided 2018-03-20 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.548G>A at the cDNA level, p.Gly183Asp (G183D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant was observed to co-occur in trans with another pathogenic MUTYH variant in an individual reported to have familial adenomatous polyposis (Skrzypczak 2006). MUTYH Gly183Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Gly183Asp is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider MUTYH Gly183Asp to be a likely pathogenic variant. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.?
Invitae RCV000456187 SCV000545737 uncertain significance MYH-associated polyposis 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 183 of the MUTYH protein (p.Gly183Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs587781864, ExAC 0.02%). This variant has been reported in two siblings affected with familial adenomatous polyposis (FAP) (PMID: 20223003). In this family the variant co-occurs with a second pathogenic variant in MUTYH. This variant also has been observed in trans with a second pathogenic MUTYH variant in an individual with colon cancer (Invitae). It is also known as 506G>A (G169D) in the literature. ClinVar contains an entry for this variant (Variation ID: 141595). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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