Submissions for variant NM_006231.4(POLE):c.6658-7C>A

gnomAD frequency: 0.00011  dbSNP: rs531482240

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657141	SCV000261970	likely benign	not provided	2025-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000657141	SCV000570900	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing	In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480223	SCV000602086	likely benign	not specified	2017-03-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000203683	SCV000784817	likely benign	Colorectal cancer, susceptibility to, 12	2016-12-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257510	SCV002536923	benign	Hereditary cancer-predisposing syndrome	2020-12-30	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000480223	SCV002572139	uncertain significance	not specified	2022-08-18	criteria provided, single submitter	clinical testing	Variant summary: POLE c.6658-7C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-05 in 249430 control chromosomes (gnomAD), predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. To our knowledge, no occurrence of c.6658-7C>A in individuals affected with Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, Genital Anomalies, And Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, four as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000480223	SCV005872670	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529000	SCV000806846	likely benign	POLE-related disorder	2020-07-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GenomeConnect, ClinGen	RCV000657141	SCV000840297	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.