ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.821G>A (p.Arg274Gln) (rs149866955)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129219 SCV000183970 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034681 SCV000043375 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000129219 SCV000902654 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Counsyl RCV000123156 SCV000487372 uncertain significance MYH-associated polyposis 2016-08-15 criteria provided, single submitter clinical testing
GeneDx RCV000034681 SCV000211407 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.821G>A at the cDNA level, p.Arg274Gln (R274Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also known as Arg260Gln using an alternate transcript, has been observed in the compound heterozygous state with a pathogenic MUTYH variant in one individual for whom the clinical history was not reported (Win 2014). It has also been observed in the single heterozygous state in individuals with colorectal cancer and/or polyps as well as breast, prostate, and other cancers (Cleary 2009, Tung 2016, Mandelker 2017, Ricci 2017). Functional studies have demonstrated reduced but partially retained glycosylation (Ali 2008, Forsbring 2009). MUTYH Arg274Gln was observed at an allele frequency of 0.04% (45/125,728) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the APE1 binding domain (Parker 2001, Yang 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg274Gln 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.
Integrated Genetics/Laboratory Corporation of America RCV000034681 SCV000697712 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing
Invitae RCV000123156 SCV000166460 uncertain significance MYH-associated polyposis 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 274 of the MUTYH protein (p.Arg274Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs149866955, ExAC 0.04%). This variant has been reported in individuals affected with colorectal cancer (CRC), colorectal polyps, or primary sclerosing cholangitis (PMID: 11818965, 19443904, 24444654, 19245865, 26202870, 29458332). In an individual affected with CRC, this variant has been observed with a pathogenic variant (p.Gly396Asp) in the MUTYH gene (PMID: 24444654). This variant is also known as Arg260Gln and c.812G>A, Arg271Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 41764). Experimental studies have shown that this variant results in reduced or defective glycosylase and DNA binding activity in vitro (PMID: 18534194, 19443904). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000613933 SCV000711715 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Arg274Gln variant in MUTYH has been reported in the heterozygous state in 11 patients with colorectal cancer (one with a pathogenic variant in MSH2), colo rectal polyps, or primary sclerosing cholangitis (Al-Tassan 2002, Forsbring 2009 , Johnston 2012, Win 2014, Win 2015). One study investigating the risk of develo ping colorectal cancer (CRC) in individuals with monoallelic and biallelic MUTYH variants reported the p.Arg274Gln variant with another pathogenic variant (Gly3 96Asp) in the biallelic state in one individual (Win 2014). Although no clinical details were provided, the authors reported near complete penetrance for bialle lic MUTYH variant carriers, making it likely that the individual had CRC. In vit ro functional studies provide some evidence that this variant results in impaire d glycosylase and DNA binding activity (Ali 2008, Forsbring 2009). However, thes e types of assays may not accurately represent biological function. This variant has been also been identified in 28/65298 of European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs149866955) . Although this variant has been seen in the general population, its frequency i s not high enough to rule out a pathogenic role. Arginine (Arg) at position 274 is not conserved in mammals or evolutionarily distant species and the change to glutamine (Gln) is present in 2 mammals (lesser Egyptian jerboa and cape elephan t shrew), raising the possibility that this change may be tolerated. Additional computational tools suggest that the p.Arg274Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg274Gln variant is uncertain.
PreventionGenetics RCV000034681 SCV000806368 uncertain significance not provided 2017-05-04 criteria provided, single submitter clinical testing

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