ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.847A>G (p.Met283Val) (rs876659676)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216419 SCV000276384 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbSNP, ESP, 1000 Genomes),in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function by in vitro/ex vivo assay,Other data supporting pathogenic classification
Color RCV000216419 SCV000911616 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing
GeneDx RCV000479475 SCV000567803 pathogenic not provided 2015-09-08 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.847A>G at the cDNA level, p.Met283Val (M283V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant, also published as MUTYH c.805A>G and p.Met269Val as well as c.763A>G and p.Met255Val, has been observed in a compound heterozygous state in three individuals, two of whom were siblings; one was reported to have a history of cecal cancer and the other two had multiple adenomatous polyps (Lejeune 2006, van Puijenbroek 2008). Additionally, MUTYH Met283Val has been shown to severely reduce gycosylase activity in vitro and the ability of MUTYH to repair 8-hydroxyguanine induced DNA damage in human cells compared to wild type controls (Goto 2010, Shinmura 2012). MUTYH Met283Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. MUTYH Met283Val occurs at a position that is conserved across species and is located in the FeS cluster (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.Although this variant is considered pathogenic, a second mutation, as would be required for expression of the recessive condition MAP, was not detected in this individual. The possibility that this patient harbors a second disease-causing MUTYH mutation that is undetectable by this test cannot be excluded. While a single variant in the MUTYH gene has been reported in association with a slightly increased risk for colon cancer, endometrial cancer, and breast cancer, particularly among those with a family history of colorectal cancer (Jenkins 2006, Win 2011, Rennert 2012), there are conflicting data regarding these associations (Santonocito 2011, Out 2012). MUTYH-associated polyposis (MAP) is an autosomal recessive condition caused by two mutations (one affecting each allele) in the MUTYH gene which results in an increased risk for the development of colon cancer and colon polyps. If a MUTYH mutation carrier'spartner is also heterozygous for a MUTYH mutation, the risk to have a child with MAP is 25% with each pregnancy. One study from the UK estimated the overall carrier frequency for any MUTYH mutation to be about 2% (Aretz 2010).
Invitae RCV000536194 SCV000639358 likely pathogenic MYH-associated polyposis 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 283 of the MUTYH protein (p.Met283Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to co-occur with another MUTYH variant in individuals affected with MUTYH-associated polyposis including evidence of segregation in one family (PMID: 18172263, 16941501). ClinVar contains an entry for this variant (Variation ID: 232291). Experimental studies have shown that this missense change impairs the glycosylase activity and the suppression of oxidative mutagenesis activity of the encoded protein (PMID: 20848659, 23322991). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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