Submissions for variant NM_006231.3(POLE):c.4237G>A (p.Glu1413Lys) (rs372901803)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079665	SCV000289371	likely benign	Colorectal cancer, susceptibility to, 12	2019-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000487363	SCV000569654	likely benign	not specified	2017-10-27	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.
PreventionGenetics,PreventionGenetics	RCV000679632	SCV000806776	uncertain significance	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000487363	SCV000920078	likely benign	not specified	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: POLE c.4237G>A (p.Glu1413Lys) results in a conservative amino acid change in 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 0.00031 in 277202 control chromosomes (gnomAD). The observed variant frequency is approximately 21.59 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.4237G>A has been reported in the literature in individual(s) affected with advanced cancer without strong evidence for causality; the variant was classified by the authors of the study as uncertain significance (Mandelker_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679632	SCV001134724	benign	not provided	2019-07-08	criteria provided, single submitter	clinical testing

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