Submissions for variant NM_006231.4(POLE):c.2469-15G>A

gnomAD frequency: 0.07057  dbSNP: rs5744833

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438788	SCV000518028	benign	not specified	2015-11-11	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586683	SCV000698666	benign	not provided	2016-05-24	criteria provided, single submitter	clinical testing	Variant summary: c.2469-15G>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 have a major effect normal on 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 0.022 (2623/120098 chrs tested), predominantly in individuals of African descent 0.237 (2429/10264 chrs tested), including numerous homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00001%, suggesting that it is a benign polymorphism. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000438788	SCV000806748	benign	not specified	2016-11-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586683	SCV001733366	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000438788	SCV002550141	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450974	SCV002738251	benign	Hereditary cancer-predisposing syndrome	2015-05-19	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001523622	SCV004016689	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000586683	SCV005237689	benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356409	SCV001551570	benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE c.2469-15G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs5744833) as "With Benign allele” and ClinVar (classified as benign by GeneDx and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 6160 of 276308 chromosomes (636 homozygous) at a frequency of 0.02, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5539 of 23994 chromosomes (freq: 0.23), Other in 64 of 6450 chromosomes (freq: 0.01), Latino in 406 of 34410 chromosomes (freq: 0.01), European in 134 of 126316 chromosomes (freq: 0.001), Ashkenazi Jewish in 9 of 10138 chromosomes (freq: 0.0008), and South Asian in 8 of 30770 chromosomes (freq: 0.0003); it was not observed in the East Asian or Finnish populations. 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 this variant meets our laboratory's criteria to be classified as benign.