ClinVar Miner

Submissions for variant NM_012222.2(MUTYH):c.1004_1005delinsGC (p.Gln335Arg) (rs587780083)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001534582 SCV000149663 likely benign not provided 2020-06-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26976419, 27153395, 25820570, 19836313)
Invitae RCV001081431 SCV000285913 likely benign MYH-associated polyposis 2020-12-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115754 SCV000601625 uncertain significance not specified 2017-01-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771092 SCV000902681 likely benign Hereditary cancer-predisposing syndrome 2016-05-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000115754 SCV001338117 uncertain significance not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1013_1014delinsGC (p.Gln338Arg) results in a conservative amino acid change in the encoded protein sequence. Two of two in-silico tools predict a benign effect of the variant on protein function. The variant was present in 34/263624 control chormosomes via gnomad. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.00013 vs 0.0046), allowing no conclusion about variant significance. c.1013_1014delinsGC has been reported in the literature in individuals affected with breast and colon cancer (Tung_2016, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. Functional evaluation of Gln338Arg (based on a different nucleotide change in at least one study) showed the variant, despite a reduced glycosylase activity, was able to complement for E. coli MutY in the rifampicin assay suggesting the enzyme to be functionally able to reduce mutations (Kundu_2009, Komine_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, three classified as likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.

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