Submissions for variant NM_006231.4(POLE):c.2026+9C>T

gnomAD frequency: 0.00038  dbSNP: rs373790607

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409224	SCV000489466	likely benign	Colorectal cancer, susceptibility to, 12	2016-10-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000425321	SCV000521642	likely benign	not specified	2017-07-19	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	RCV000759268	SCV000556412	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759268	SCV000888500	benign	not provided	2018-12-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257665	SCV002536770	benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000409224	SCV004017067	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000425321	SCV004027352	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000425321	SCV004028992	benign	not specified	2023-07-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002257665	SCV004849228	uncertain significance	Hereditary cancer-predisposing syndrome	2015-08-06	criteria provided, single submitter	clinical testing	The c.2026+9C>T intronic alteration consists of a C to T substitution nucleotides after coding exon 18 in the POLE gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004529565	SCV000806735	benign	POLE-related disorder	2019-05-15	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355770	SCV001550742	likely benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE c.2026+9C>T variant was not identified in the literature. The variant was identified in dbSNP (ID: rs373790607) as "With other allele ", and in ClinVar (classified as benign by Invitae; as likely benign Counsyl, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was identified in control databases in 104 of 276484 chromosomes (1 homozygous) at a frequency of 0.0004 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 5 of 23998 chromosomes (freq: 0.0002), Latino in 10 of 34348 chromosomes (freq: 0.0003), European in 53 of 126330 chromosomes (freq: 0.0004), and South Asian in 36 of 30722 chromosomes (freq: 0.001); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, and Finnish populations. 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000759268	SCV001807689	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000425321	SCV001918595	benign	not specified		no assertion criteria provided	clinical testing