ClinVar Miner

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

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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 RCV000216419 SCV000276384 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-22 criteria provided, single submitter clinical testing The p.M283V variant (also known as c.847A>G), located in coding exon 10 of the MUTYH gene, results from an A to G substitution at nucleotide position 847. The methionine at codon 283 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in conjunction with a MUTYH pathogenic mutation in patients with multiple adenomas and/or colorectal cancer (Lejeune S et al, Hum. Mutat. 2006 Oct; 27(10):1064; van Puijenbroek M et al. Clin Cancer Res. 2008 Jan 1;14(1):139-42). In addition, functional studies have shown this alteration causes severe impairment in DNA glycosylase activity compared to the wild-type protein (Goto M et al. Hum. Mutat. 2010 Nov; 31(11):E1861-74); as well as suppression of oxidative mutagenesis, thought to severely impair function in human cells (Shinmura K et al. World J. Gastroenterol. 2012 Dec; 18(47):6935-42). Of note, this alteration is also designated as p.M269V (c.805A>G) in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.
Color Health, Inc RCV000216419 SCV000911616 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-03 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355443 SCV001550329 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Met283Val variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer or cecum carcinoma (Lejeune 2006, Puijenbroek 2008). The variant was also identified in dbSNP (ID: rs876659676) as "With Pathogenic allele", ClinVar (classified as likely pathogenic by Ambry Genetics and Invitae; as pathogenic by GeneDx), Clinvitae, and in UMD-LSDB (10x as unclassified variant). In UMD the variant was identified with co-occurring pathogenic MUTYH variants (c.1059dup (p.Arg354GlnfsX164) and c.1105delC (p.Ala371ProfsX23)). The variant was not identified in the COGR, Cosmic, or MutDB databases. The variant was identified in control databases in 1 of 245722 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) in 1 of 111308 chromosomes (freq: 0.00001); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, Other, and South Asian populations. Several In vitro studies show that this variant severely reduces gycosylase activity. The variant protein exhibited only 4.5% of the glycosylase activity of the wild-type protein, which is more than 20-fold lower than that of the wildtype protein (Goto 2010, Shinmura 2012). The p.Met283 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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