ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.123G>A (p.Thr41=)

gnomAD frequency: 0.00320  dbSNP: rs5744734
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079678 SCV000289246 benign Colorectal cancer, susceptibility to, 12 2022-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000759260 SCV000521364 likely benign not provided 2021-09-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563676 SCV000671309 benign Hereditary cancer-predisposing syndrome 2015-06-27 criteria provided, single submitter clinical testing This alteration is classified as 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.
PreventionGenetics, PreventionGenetics RCV000422401 SCV000806713 benign not specified 2017-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759260 SCV000888488 benign not provided 2018-09-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000422401 SCV001363593 benign not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: POLE c.123G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 277224 control chromosomes, predominantly at a frequency of 0.01 within the African subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 704 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.123G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago RCV000422401 SCV002071616 likely benign not specified 2021-06-07 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000563676 SCV000788159 likely benign Hereditary cancer-predisposing syndrome 2017-10-25 no assertion criteria provided clinical testing

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