ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.881G>A (p.Arg294His) (rs146044717)

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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 RCV000213855 SCV000274056 likely benign Hereditary cancer-predisposing syndrome 2019-03-30 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other strong data
Invitae RCV000457374 SCV000545780 uncertain significance MYH-associated polyposis 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 294 of the MUTYH protein (p.Arg294His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs146044717, ExAC 0.01%). This variant has not been reported in the literature in individuals with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 230487). 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 histidine 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 RCV000485598 SCV000565260 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.881G>A at the cDNA level, p.Arg294His (R294H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Arg294His was not observed at a significant allele frequency 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Arg294His 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.
Color Health, Inc RCV000213855 SCV000903157 likely benign Hereditary cancer-predisposing syndrome 2016-09-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001293539 SCV001482135 uncertain significance not specified 2021-02-08 criteria provided, single submitter clinical testing Variant summary: MUTYH c.881G>A (p.Arg294His) results in a non-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 4.8e-05 in 251108 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (4.8e-05 vs 0.0046), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.881G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

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