Submissions for variant NM_006231.3(POLE):c.123G>A (p.Thr41=) (rs5744734)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079678	SCV000289246	benign	Colorectal cancer, susceptibility to, 12	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000422401	SCV000521364	likely benign	not specified	2017-12-21	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.
Ambry Genetics	RCV000563676	SCV000671309	benign	Hereditary cancer-predisposing syndrome	2015-06-27	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
PreventionGenetics,PreventionGenetics	RCV000422401	SCV000806713	benign	not specified	2017-08-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759260	SCV000888488	benign	not provided	2018-09-11	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000422401	SCV001363593	benign	not specified	2019-04-01	criteria provided, single submitter	clinical testing	Variant summary: POLE c.123G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 277224 control chromosomes, predominantly at a frequency of 0.01 within the African subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 704 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 origin. To our knowledge, no occurrence of c.123G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
True Health Diagnostics	RCV000563676	SCV000788159	likely benign	Hereditary cancer-predisposing syndrome	2017-10-25	no assertion criteria provided	clinical testing