ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.326G>C (p.Arg109Pro) (rs761763725)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532016 SCV000639309 uncertain significance MYH-associated polyposis 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 109 of the MUTYH protein (p.Arg109Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs761763725, ExAC 0.01%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 464711). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg109 amino acid residue in MUTYH have been observed in affected individuals (PMID: 19732775, 21520333, 24799981, 25980754). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Ambry Genetics RCV001019554 SCV001180928 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-27 criteria provided, single submitter clinical testing The p.R109P variant (also known as c.326G>C), located in coding exon 3 of the MUTYH gene, results from a G to C substitution at nucleotide position 326. The arginine at codon 109 is replaced by proline, an amino acid with dissimilar properties. This variant was detected in conjunction with a pathogenic MUTYH founder mutation in an individual with colonic polyposis (Ambry internal data). Another alteration at the same codon, p.R109W, has been classified as likely pathogenic based on instances of co-occurrence with pathogenic MUTYH mutations in patients with adenomatous polyposis and reduced MUTYH protein activity in a functional assay (Ambry internal data; Vogt et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10; Shinmura K et al. Oxid. Med. Cell Longev. 2014 Mar;2014:617351). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.
Color Health, Inc RCV001019554 SCV001357726 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing

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