Submissions for variant NM_006231.4(POLE):c.3379-5T>C

gnomAD frequency: 0.02670  dbSNP: rs5744886

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437378	SCV000518019	benign	not specified	2015-11-06	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	RCV000437378	SCV000540084	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: Frequency
Invitae	RCV000590570	SCV000556425	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492126	SCV000581377	benign	Hereditary cancer-predisposing syndrome	2015-05-20	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590570	SCV000698671	benign	not provided	2016-05-19	criteria provided, single submitter	clinical testing	Variant summary: c.3379-5T>C in POLE gene is an intronic change that involves a non-conserved nucleotide. The variant is present in the control population dataset of ExAC at frequency of 0.0333 (3963/118996 chrs tested), predominantly in individuals of Latin descent (0.17; 1945/11380 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0014%, suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports or cited by reputable databases/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	RCV000437378	SCV000806761	benign	not specified	2016-11-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590570	SCV001473527	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000437378	SCV002550118	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001079607	SCV004016699	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000492126	SCV000788175	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000437378	SCV001551156	benign	not specified		no assertion criteria provided	clinical testing	The POLE c.3379-5T>C variant was not identified in the literature, Cosmic, MutDB, or LOVD 3.0. The variant was identified in dbSNP (ID: rs5744886) as “With Benign allele” and ClinVar (classified benign by GeneDx, Laboratory for Molecular Medicine/Partners HealthCare Personalized Medicine, Invitae, and Ambry Genetics). The variant was also identified in control databases in 10094 (549 homozygous) of 276806 chromosomes at a frequency of 0.04 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5548 (480 homozygous) of 34370 chromosomes (freq: 0.2), African in 136 of 24016 chromosomes (freq: 0.006), Other in 229 (8 homozygous) of 6464 chromosomes (freq: 0.04), European in 3101 (46 homozygous) of 126470 chromosomes (freq: 0.02), Ashkenazi Jewish in 71 (1 homozygous) of 10144 chromosomes (freq: 0.007), East Asian in 4 of 18868 chromosomes (freq: 0.0002), Finnish in 790 (13 homozygous) of 25700 chromosomes (freq: 0.03), and South Asian in 215 (1 homozygous) of 30774 chromosomes (freq: 0.007). The c.3379-5T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, 5 of 5 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	RCV000437378	SCV001807272	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000437378	SCV001924508	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000437378	SCV001926761	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000437378	SCV002036427	benign	not specified		no assertion criteria provided	clinical testing