Submissions for variant NM_001048174.2(MUTYH):c.929_930delinsGC (p.Gln310Arg)

dbSNP: rs587780083

Total submissions: 6

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	Familial adenomatous polyposis 2	2024-02-01	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 Diagnostics, LLC DBA Color Health	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	2023-04-03	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. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 263932 control chromosomes (gnomAD). This frequency is not significantly higher than estimated 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 (example: 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 (example: Kundu_2009, Komine_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV000771092	SCV002623311	likely benign	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.