ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.4184A>G (p.Tyr1395Cys) (rs5744933)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226045 SCV000289369 benign not provided 2016-03-04 criteria provided, single submitter clinical testing
GeneDx RCV000256131 SCV000322483 likely benign not specified 2018-03-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256131 SCV000602042 uncertain significance not specified 2017-01-12 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000256131 SCV000806774 benign not specified 2017-10-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000256131 SCV000918086 benign not specified 2018-07-13 criteria provided, single submitter clinical testing Variant summary: POLE c.4184A>G (p.Tyr1395Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 277082 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 52-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 benign. To our knowledge, no occurrence of c.4184A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x likely benign/benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign.

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