ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.530G>A (p.Arg177Gln) (rs369677603)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212702 SCV000149677 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.572G>A at the cDNA level, p.Arg191Gln (R191Q) 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 a pathogenic or benign germline variant. MUTYH Arg191Gln was observed at an allele frequency of 0.11% (11/9850) in large population cohorts (Lek 2016). MUTYH Arg191Gln 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 Arg191Gln is pathogenic or benign. 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.
Ambry Genetics RCV000115768 SCV000183833 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-05 criteria provided, single submitter clinical testing The p.R191Q variant (also known as c.572G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 572. The arginine at codon 191 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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 RCV000168022 SCV000218674 uncertain significance MYH-associated polyposis 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 191 of the MUTYH protein (p.Arg191Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs369677603, ExAC 0.009%). This variant has been observed in individual(s) undergoing testing for hereditary cancer predisposition (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 127846). 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.
Counsyl RCV000168022 SCV000799307 uncertain significance MYH-associated polyposis 2018-04-09 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115768 SCV000822075 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212702 SCV000888319 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765176 SCV000896409 uncertain significance MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115768 SCV000902721 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192928 SCV001361389 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MUTYH c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251474 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.4e-05 vs 0.0046), allowing no conclusion about variant significance. c.572G>A has been reported in the literature in a cohort of individuals under going genetic testing (exact phenotype of the reported individual was not provided)(Tsaousis_2019). This report does not provide an unequivocal conclusion about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant seven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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