ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.347G>A (p.Arg116Gln) (rs587782683)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132110 SCV000187176 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing The p.R116Q variant (also known as c.347G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 347. The arginine at codon 116 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000197990 SCV000254710 uncertain significance MYH-associated polyposis 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 116 of the MUTYH protein (p.Arg116Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782683, ExAC 0.003%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 142736). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000479477 SCV000570382 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.347G>A at the cDNA level, p.Arg116Gln (R116Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Arg116Gln was observed at an allele frequency of 0.03% (9/34420) in individuals of Latino ancestry 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Arg116Gln 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.
Fulgent Genetics,Fulgent Genetics RCV000515197 SCV000611407 uncertain significance MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479477 SCV000888314 uncertain significance not provided 2020-05-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132110 SCV000903449 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-12 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 116 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 17/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780501 SCV000917806 uncertain significance not specified 2019-03-26 criteria provided, single submitter clinical testing Variant summary: MUTYH c.347G>A (p.Arg116Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 277200 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.1e-05 vs 0.0046), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.347G>A in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000197990 SCV001481307 uncertain significance MYH-associated polyposis 2020-12-04 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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