ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.509G>A (p.Arg170Gln) (rs758567247)

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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 RCV000167475 SCV000218332 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing The p.R184Q variant (also known as c.551G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 551. The arginine at codon 184 is replaced by glutamine, an amino acid with highly similar properties. This alteration (designated as p.R170Q) was detected in one Korean individual with seven colorectal polyps and was not detected in 300 controls (Kim JC et al. Virchows Arch. 2007 Mar;450(3):311-9). This alteration was also detected in 1/299 Italian patients who underwent clinical testing for multiple adenomatous polyposis (Ricci MT et al. J. Hum. Genet. 2017 Feb;62(2):309-315). This amino acid position is well conserved in available 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.
GeneDx RCV000482615 SCV000568582 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.551G>A at the cDNA level, p.Arg184Gln (R184Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also denoted MYH R170Q using alternate nomenclature, was observed in individuals with adenomatous colorectal polyps and/or colorectal cancer (Kim 2007, Ricci 2017). MUTYH Arg184Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg184Gln 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 pathogenic variants on opposite chromosomes in MUTYH.?
Invitae RCV000557996 SCV000639340 uncertain significance MYH-associated polyposis 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 184 of the MUTYH protein (p.Arg184Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs758567247, ExAC 0.01%). This variant has been reported in an individual affected with multiple colorectal adenomas (PMID: 17252231), and an individual with suspected MUTYH-associated polyposis (PMID: 27829682). This variant is also known as MYH R170Q in the literature. ClinVar contains an entry for this variant (Variation ID: 187723). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000167475 SCV000685641 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-03 criteria provided, single submitter clinical testing
Counsyl RCV000557996 SCV000789004 uncertain significance MYH-associated polyposis 2016-12-28 criteria provided, single submitter clinical testing

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