ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.5135C>T (p.Ala1712Val) (rs5744950)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567511 SCV000671264 likely benign Hereditary cancer-predisposing syndrome 2015-06-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
GeneDx RCV000442571 SCV000518910 likely benign not specified 2018-01-02 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.
Integrated Genetics/Laboratory Corporation of America RCV000442571 SCV000918084 benign not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: POLE c.5135C>T (p.Ala1712Val) results in a non-conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.001 in 270890 control chromosomes (gnomAD), predominantly in the African cohort at an allele frequency of 0.011 (264/23978 chromosomes). The observed variant frequency within African control individuals in the gnomAD database is approximately 774-folds higher than 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.5135C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000204376 SCV000262287 benign Colorectal cancer, susceptibility to, 12 2018-01-13 criteria provided, single submitter clinical testing
PreventionGenetics RCV000679642 SCV000806796 likely benign not provided 2018-01-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000442571 SCV000602062 benign not specified 2017-04-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679642 SCV000889768 benign not provided 2017-04-27 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000567511 SCV000788183 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing

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