Submissions for variant NM_006231.4(POLE):c.4237G>A (p.Glu1413Lys)

gnomAD frequency: 0.00014  dbSNP: rs372901803

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679632	SCV000289371	likely benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000679632	SCV000569654	likely benign	not provided	2021-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Genetic Services Laboratory, University of Chicago	RCV000487363	SCV002066979	uncertain significance	not specified	2019-12-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257582	SCV002536839	likely benign	Hereditary cancer-predisposing syndrome	2021-03-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000487363	SCV004243488	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002257582	SCV005481522	likely benign	Hereditary cancer-predisposing syndrome	2024-06-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV004529406	SCV000806776	uncertain significance	POLE-related disorder	2024-02-16	no assertion criteria provided	clinical testing	The POLE c.4237G>A variant is predicted to result in the amino acid substitution p.Glu1413Lys. This variant was reported in a study of individuals with advanced cancer, however specific details were not provided (eTable, Mandelker et al. 2017. PubMed ID: 28873162). This variant is reported in 0.32% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which may be too common to be causative. In Clinvar, this variant has conflicting interpretations, ranging from uncertain significance to likely benign, to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/240507/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679632	SCV001549972	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLE p.Glu1413Lys variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals or families with unspecified cancer (Mandelker 2017). The variant was also identified in dbSNP (ID: rs372901803) as "With Likely benign allele", in ClinVar (classified as likely benign by Invitae and GeneDx; as uncertain significance by Prevention Genetics). The variant was identified in control databases in 85 of 277202 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 44 of 34418 chromosomes (freq: 0.001), European Non-Finnish in 6 of 126690 chromosomes (freq: 0.00005), Ashkenazi Jewish in 34 of 10152 chromosomes (freq: 0.003); it was not observed in the African, East Asian, Finnish, and South Asian populations. The p.Glu1413 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.