Submissions for variant NM_006231.4(POLE):c.850A>G (p.Lys284Glu)

gnomAD frequency: 0.00002  dbSNP: rs568483856

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000481268	SCV000544043	uncertain significance	not provided	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 284 of the POLE protein (p.Lys284Glu). This variant is present in population databases (rs568483856, gnomAD 0.02%). This missense change has been observed in individual(s) with multiple colon polyps (PMID: 25938944). ClinVar contains an entry for this variant (Variation ID: 405725). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000481268	SCV000569492	uncertain significance	not provided	2024-10-29	criteria provided, single submitter	clinical testing	Observed in an individual with multiple adenomatous polyps and in another individual with colon cancer who also carried a pathogenic variant in PMS2 (PMID: 25938944, 29596542); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25938944, 28492532, 28404093, 29596542, 30448219)
Ambry Genetics	RCV000561911	SCV000671535	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	The p.K284E variant (also known as c.850A>G), located in coding exon 9 of the POLE gene, results from an A to G substitution at nucleotide position 850. The lysine at codon 284 is replaced by glutamic acid, an amino acid with similar properties. In a study of 51 individuals with multiple colonic adenomas from 48 families who underwent whole-exome sequencing, this variant was identified in a patient with a mix of 30 adenomatous, hyperplastic, and serrated polyps who did not have first degree relatives with colorectal cancer or polyps (Weren RD et al. Nat. Genet. 2015 Jun;47:668-71). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000461936	SCV000785629	uncertain significance	Colorectal cancer, susceptibility to, 12	2017-10-17	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465654	SCV002760966	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000461936	SCV004018519	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000461936	SCV004203527	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-10-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002465654	SCV005203620	uncertain significance	not specified	2024-07-05	criteria provided, single submitter	clinical testing	Variant summary: POLE c.850A>G (p.Lys284Glu) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251454 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.850A>G has been reported in the literature in settings of whole exome sequencing (WES) performed in at-least one individual affected with Colorectal Cancer highly suspected of a hereditary cause (example, Weren_2015). These report(s) 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. The following publication have been ascertained in the context of this evaluation (PMID: 25938944). ClinVar contains an entry for this variant (Variation ID: 405725). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481268	SCV005625188	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	The POLE c.850A>G (p.Lys284Glu) variant has been reported in the published literature in individuals affected with ovarian cancer (PMIDs: 32546565 (2021), 30448219 (2019)), colorectal cancer (PMID: 30877237 (2019)), as well as in reportedly healthy individuals (PMID: 29641532 (2018)). The frequency of this variant in the general population, 0.00016 (4/25116 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004737500	SCV005348215	uncertain significance	POLE-related disorder	2024-07-29	no assertion criteria provided	clinical testing	The POLE c.850A>G variant is predicted to result in the amino acid substitution p.Lys284Glu. This variant was reported in an individual with colorectal cancer and adenomatous polyposis in the absence of other known pathogenic variants (Weren et al. 2015. PubMed ID: 25938944). This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD and is classified as a variant on uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/405725/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.