Submissions for variant NM_006231.4(POLE):c.2468+10C>T

gnomAD frequency: 0.00342  dbSNP: rs5744823

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679615	SCV000262286	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000206477	SCV000489444	likely benign	Colorectal cancer, susceptibility to, 12	2016-10-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000434825	SCV000518909	likely benign	not specified	2017-06-29	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000434825	SCV000889726	benign	not specified	2017-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000434825	SCV000918085	benign	not specified	2018-07-10	criteria provided, single submitter	clinical testing	Variant summary: POLE c.2468+10C>T 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. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.001 in 276194 control chromosomes (gnomAD), predominantly in the African cohort with an allele frequency of 0.012. The observed variant frequency within African control individuals in the gnomAD database is approximately 774-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.2468+10C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679615	SCV001157649	benign	not provided	2022-11-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000434825	SCV002071559	benign	not specified	2017-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444833	SCV002733893	likely benign	Hereditary cancer-predisposing syndrome	2015-10-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Fulgent Genetics, Fulgent Genetics	RCV002500663	SCV002811760	likely benign	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2022-05-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000206477	SCV004017084	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529004	SCV000806747	benign	POLE-related disorder	2019-09-04	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	RCV001356143	SCV001551217	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE c.2468+10C>T variant was not identified in the literature. The variant was identified in dbSNP (ID: rs5744823) as "With other allele ", and in ClinVar database (classified as benign by Invitae and one clinical laboratory; as likely benign by Counsyl, GeneDx, and Prevention Genetics). The variant was identified in control databases in 284 of 276194 chromosomes at a frequency of 0.001 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 263 of 24008 chromosomes (freq: 0.01), Other in 2 of 6436 chromosomes (freq: 0.0003), Latino in 19 of 34346 chromosomes (freq: 0.0006), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, and South Asian 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 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.