ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.1007A>G (p.Asn336Ser) (rs5744760)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230914 SCV000289233 benign Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000427188 SCV000519163 likely benign not specified 2017-12-12 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 RCV000427188 SCV000601968 benign not specified 2016-09-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573616 SCV000671265 benign Hereditary cancer-predisposing syndrome 2015-05-19 criteria provided, single submitter clinical testing
Counsyl RCV000230914 SCV000785512 benign Colorectal cancer, susceptibility to, 12 2017-09-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000427188 SCV000806708 benign not specified 2016-12-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759255 SCV000888483 benign not provided 2016-09-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000427188 SCV000918082 benign not specified 2018-06-15 criteria provided, single submitter clinical testing Variant summary: POLE c.1007A>G (p.Asn336Ser) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 121118 control chromosomes in the ExAC database, including 5 homozygotes. The observed variant frequency is approximately 189.49 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.1007A>G 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/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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