Submissions for variant NM_006231.4(POLE):c.4259C>T (p.Ala1420Val)

gnomAD frequency: 0.00325  dbSNP: rs41561818

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679633	SCV000261558	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000444652	SCV000517997	benign	not specified	2017-12-08	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.
Ambry Genetics	RCV000572485	SCV000671225	likely benign	Hereditary cancer-predisposing syndrome	2015-06-18	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.
Counsyl	RCV000203869	SCV000786284	likely benign	Colorectal cancer, susceptibility to, 12	2018-04-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000444652	SCV000888536	benign	not specified	2018-02-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000203869	SCV001138869	likely benign	Colorectal cancer, susceptibility to, 12	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679633	SCV001157640	benign	not provided	2023-09-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679633	SCV001249335	likely benign	not provided	2025-03-01	criteria provided, single submitter	clinical testing	POLE: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000444652	SCV001774514	benign	not specified	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: POLE c.4259C>T (p.Ala1420Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 251382 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 246 fold of 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 benign. To our knowledge, no occurrence of c.4259C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000444652	SCV002550099	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494534	SCV002805553	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	2021-10-12	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000572485	SCV000788177	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528996	SCV000806777	benign	POLE-related disorder	2019-06-03	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	RCV001356655	SCV001551885	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Ala1420Val variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs41561818) as "With other allele", ClinVar (classified as benign by Invitae and GeneDx; as likely benign by five submitters), and MutDB databases. The variant was identified in control databases in 1011 of 277176 chromosomes (9 homozygous) at a frequency of 0.004, 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: Finnish in 316 of 25794 chromosomes (freq: 0.01), African in 13 of 24030 chromosomes (freq: 0.0005), Other in 21 of 6464 chromosomes (freq: 0.003), Latino in 93 of 34410 chromosomes (freq: 0.003), European in 560 of 126680 chromosomes (freq: 0.004), Ashkenazi Jewish in 7 of 10148 chromosomes (freq: 0.0007), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian population. The p.Ala1420 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000679633	SCV001798684	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000444652	SCV001809582	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000444652	SCV001922397	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679633	SCV001975498	likely benign	not provided		no assertion criteria provided	clinical testing