Submissions for variant NM_006231.4(POLE):c.2174-8G>A

gnomAD frequency: 0.01137  dbSNP: rs117409343

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586345	SCV000261617	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000424665	SCV000518044	benign	not specified	2016-11-18	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000424665	SCV000540087	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.7% European, intronic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586345	SCV000698663	benign	not provided	2016-08-17	criteria provided, single submitter	clinical testing	Variant summary: c.2174-8G>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.012 (1461/121260 chrs tested), including 4 homozygous occurrences. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.000014, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign/Polymorphism by reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000424665	SCV000806741	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586345	SCV000888511	benign	not provided	2023-02-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586345	SCV001157477	benign	not provided	2023-02-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000424665	SCV002550156	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204595	SCV004017075	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000586345	SCV005217337	likely benign	not provided		criteria provided, single submitter	not provided
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000664288	SCV005688941	benign	Hereditary cancer-predisposing syndrome	2025-01-15	criteria provided, single submitter	clinical testing	The splice region variant NM_006231.4(POLE):c.2174-8G>A has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 220785 as of 2025-01-02). The c.2174-8G>A variant is not predicted to disrupt the existing acceptor splice site 6bp upstream by any splice site algorithm. The c.2174-8G>A variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign.
True Health Diagnostics	RCV000664288	SCV000788166	likely benign	Hereditary cancer-predisposing syndrome	2018-02-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355620	SCV001550554	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE c.2174-8G>A variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs117409343) as “With other allele”, ClinVar and Clinvitae (5x as benign by Invitae, GeneDx, Quest diagnostics, Laboratory Corporation of America and likely benign by Laboratory for molecular Medicine). The variant was identified in control databases in 3277 of 276912 chromosomes (25 homozygous) at a frequency of 0.012 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 75 of 24034 chromosomes (freq: 0.003), Other in 88 of 6458 chromosomes (freq: 0.013), Latino in 291 of 34418 chromosomes (freq: 0.008), European Non-Finnish in 2146 of 126616 chromosomes (freq: 0.017), Ashkenazi Jewish in 87 of 10152 chromosomes (freq: 0.008), East Asian in 1 of 18870 chromosomes (freq: 0.000053), European Finnish in 502 of 25584 chromosomes (freq: 0.02), and South Asian in 87 of 30780 chromosomes (freq: 0.003). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000424665	SCV001808532	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000424665	SCV001917672	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000586345	SCV002036643	likely benign	not provided		no assertion criteria provided	clinical testing