ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.3747G>A (p.Val1249=) (rs80290414)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079711 SCV000289341 benign Colorectal cancer, susceptibility to, 12 2019-12-30 criteria provided, single submitter clinical testing
GeneDx RCV000425953 SCV000524201 likely benign not specified 2017-12-21 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 RCV000228096 SCV000602033 benign not provided 2019-08-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567729 SCV000671347 likely benign Hereditary cancer-predisposing syndrome 2015-06-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000425953 SCV001361243 benign not specified 2019-01-02 criteria provided, single submitter clinical testing Variant summary: The variant, POLE c.3747G>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 0.00028 in 277050 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0032 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 225 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.3747G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (x1) or likely benign (X3). Based on the evidence outlined above, the variant was classified as benign.

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