ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.2089C>T (p.Pro697Ser) (rs5744800)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083123 SCV000289286 benign Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000424622 SCV000521330 benign not specified 2018-01-09 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 RCV000424622 SCV000601994 likely benign not specified 2017-03-21 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514900 SCV000610570 likely benign not provided 2017-07-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569482 SCV000671230 likely benign Hereditary cancer-predisposing syndrome 2015-06-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
PreventionGenetics,PreventionGenetics RCV000424622 SCV000806738 benign not specified 2017-09-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000514900 SCV000888506 benign not provided 2017-12-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000424622 SCV001362517 benign not specified 2019-11-26 criteria provided, single submitter clinical testing Variant summary: POLE c.2089C>T (p.Pro697Ser) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 250172 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 845 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 or African-American origin. To our knowledge, no occurrence of c.2089C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six 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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