Submissions for variant NM_006231.4(POLE):c.4290+5C>T

gnomAD frequency: 0.02053  dbSNP: rs5744936

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434235	SCV000518033	benign	not specified	2016-12-01	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000590621	SCV000556405	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492639	SCV000581382	benign	Hereditary cancer-predisposing syndrome	2015-05-21	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000434235	SCV000602047	benign	not specified	2016-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590621	SCV000698674	benign	not provided	2016-05-19	criteria provided, single submitter	clinical testing	Variant summary: The POLE c.4290+5C>T variant involves the alteration of a non-conserved nucleotide located in an intronic position outside of the canonical slice sites. Mutation taster predicts a damaging outcome for this variant while 5/5 in silico tools via Alamut predict the variant no to have a significant impact on splicing. The variant was found in 2827/117634 control chromosomes (40 homozygotes) at a frequency of 0.0240322, which is approximately 1692 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000434235	SCV000806778	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590621	SCV001470983	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000492639	SCV002536844	benign	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000434235	SCV002550097	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000459685	SCV004016700	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000590621	SCV005237228	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000492639	SCV000788178	likely benign	Hereditary cancer-predisposing syndrome	2018-02-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355628	SCV001550564	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE c.4290+5C>T variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs5744936) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), and in control databases in 6696 (102 homozygous) of 276312 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 94 (1 homozygous) of 24002 chromosomes (freq: 0.004), Other in 171 (1 homozygous) of 6448 chromosomes (freq: 0.03), Latino in 414 (2 homozygous) of 34364 chromosomes (freq: 0.01), European Non-Finnish in 3397 (47 homozygous) of 126076 chromosomes (freq: 0.03), Ashkenazi Jewish in 162 (1 homozygous) of 10110 chromosomes (freq: 0.02), East Asian in 626 (12 homozygous) of 18858 chromosomes (freq: 0.03), European Finnish in 1086 (27 homozygous) of 25750 chromosomes (freq: 0.04), and South Asian in 746 (11 homozygous) of 30704 chromosomes (freq: 0.02). The c.4290+5C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000434235	SCV001799475	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000590621	SCV001809055	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000434235	SCV001925067	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000434235	SCV001926598	benign	not specified		no assertion criteria provided	clinical testing