ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3046G>A (p.Val1016Met) (rs147692158)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000988944 SCV000261875 likely benign Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000585364 SCV000293081 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted POLE c.3046G>A at the cDNA level, p.Val1016Met (V1016M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in at least one individual with advanced cancer, type not specified (Mandelker 2017). POLE Val1016Met was observed at an allele frequency of 0.14% (172/124,734) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether POLE Val1016Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235475 SCV000540094 uncertain significance not specified 2016-10-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely benign by Invitae and VUS by GeneDx. It is present in ExAC at a MaxMAF of 0.15% (high for disease incidence and gene contribution).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585364 SCV000602024 benign not provided 2019-02-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562355 SCV000671246 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585364 SCV000692767 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000585364 SCV000806756 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing
Mendelics RCV000709263 SCV000838694 uncertain significance COLORECTAL CANCER 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988944 SCV001138881 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235475 SCV001361502 likely benign not specified 2019-05-14 criteria provided, single submitter clinical testing Variant summary: POLE c.3046G>A (p.Val1016Met) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 248236 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 55 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. c.3046G>A has been reported in the literature in individuals affected with various tumor phenotypes, e.g. colorectal cancer and cutaneous melanoma, but without strong evidence of causality (Dominguez-Valentin_2018, Pritchard_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classified as likely benign while the others classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
True Health Diagnostics RCV000562355 SCV000886710 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 no assertion criteria provided clinical testing

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