ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.5659G>A (p.Val1887Met) (rs114119067)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079688 SCV000289434 likely benign Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000657089 SCV000293566 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted POLE c.5659G>A at the cDNA level, p.Val1887Met (V1887M) 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 suspected of having hereditary cancer predisposition, as well as in an individual with Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) with no specific information provided about cancer history (Barclay 2015, Feliubadal? 2017). POLE Val1887Met was observed at an allele frequency of 0.1% (35/34,418) in individuals of Latino 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 Val1887Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236237 SCV000602073 uncertain significance not specified 2017-05-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000657089 SCV000806814 uncertain significance not provided 2017-09-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000657089 SCV001148878 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000236237 SCV001361239 likely benign not specified 2019-02-19 criteria provided, single submitter clinical testing Variant summary: POLE c.5659G>A (p.Val1887Met) results in a conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal 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 0.00047 in 277072 control chromosomes, predominantly at a frequency of 0.001 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 70 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 Latino origin. c.5659G>A has been reported in the literature in individuals associated with cancer phenotype and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (Gray_2018, Feliubadalo_2017, Barclay_2015). These reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories cite the variant as uncertain significance (3x) and once as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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