ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.6494G>A (p.Arg2165His) (rs5745068)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492600 SCV000581376 likely benign Hereditary cancer-predisposing syndrome 2015-05-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (benign),Subpopulation frequency in support of benign classification
Counsyl RCV000204118 SCV000488502 likely benign Colorectal cancer, susceptibility to, 12 2016-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000438859 SCV000518489 benign not specified 2017-05-17 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 RCV000438859 SCV000920072 benign not specified 2018-01-29 criteria provided, single submitter clinical testing Variant summary: POLE c.6494G>A (p.Arg2165His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0057 in 269142 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 402 fold above 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. The variant c.6494G>A has been reported in the literature in individuals affected with Colorectal Cancer. These report(s) do not provide unequivocal conclusions about the association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000204118 SCV000261708 benign Colorectal cancer, susceptibility to, 12 2018-01-10 criteria provided, single submitter clinical testing
PreventionGenetics RCV000438859 SCV000806838 benign not specified 2017-07-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000438859 SCV000602083 likely benign not specified 2017-06-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759315 SCV000888567 benign not provided 2017-08-14 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000492600 SCV000788191 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing

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