ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1226G>A (p.Arg409Gln) (rs587782120)

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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 RCV000130651 SCV000185536 likely benign Hereditary cancer-predisposing syndrome 2018-04-04 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification;Other strong data;Structural Evidence
Invitae RCV000234150 SCV000285925 uncertain significance MYH-associated polyposis 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 437 of the MUTYH protein (p.Arg437Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782120, ExAC 0.003%). This variant has been reported in individuals affected with colorectal cancer (CRC) and family history of CRC (PMID: 15943555). This variant is also known as c.1268G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 141933). An experimental study has shown that this variant preserves the ability to complement the functional deficiency in MutY-disrupted E coli, suggesting that this missense change does not adversely affect protein function (PMID: 25820570). 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.
Counsyl RCV000234150 SCV000487377 uncertain significance MYH-associated polyposis 2016-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000587516 SCV000570116 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1310G>A at the cDNA level, p.Arg437Gln (R437Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also published as MUTYH Arg423Gln (R423Q) using alternate nomenclature, has been observed in at least three individuals with sporadic colorectal cancer (Zhou 2005). An E. coli-based complementation assay found that MUTYH Arg437Gln exhibited a spontaneous mutation rate similar to wild-type controls, suggesting that this variant retains protein function (Komine 2015). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MUTYH Arg437Gln is located in the NUDIX domain (Ruggieri 2013). 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 Arg437Gln 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.?
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290443 SCV000697676 uncertain significance not specified 2021-01-16 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1310G>A (p.Arg437Gln) results in a conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) 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 7.9e-06 in 254566 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1310G>A has been reported in the literature in individuals affected with sporadic colorectal cancer (example, Zhou_2005). This report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function (example, Komine_2015). These results showed no damaging effect of this variant in an assay evaluating functional complementation in a MutY-disrupted E Coli strain. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n=5, likely benign, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000234150 SCV000837746 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130651 SCV000911085 likely benign Hereditary cancer-predisposing syndrome 2017-05-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000234150 SCV001253575 uncertain significance MYH-associated polyposis 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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