Submissions for variant NM_006231.4(POLE):c.5135C>T (p.Ala1712Val)

gnomAD frequency: 0.00346  dbSNP: rs5744950

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000679642	SCV000262287	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000442571	SCV000518910	likely benign	not specified	2018-01-02	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	RCV000567511	SCV000671264	likely benign	Hereditary cancer-predisposing syndrome	2015-06-25	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.
PreventionGenetics, part of Exact Sciences	RCV000679642	SCV000806796	likely benign	not provided	2018-01-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000442571	SCV000889768	benign	not specified	2017-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442571	SCV000918084	benign	not specified	2018-07-10	criteria provided, single submitter	clinical testing	Variant summary: POLE c.5135C>T (p.Ala1712Val) results in a non-conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.001 in 270890 control chromosomes (gnomAD), predominantly in the African cohort at an allele frequency of 0.011 (264/23978 chromosomes). 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.5135C>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	RCV000679642	SCV001157648	likely benign	not provided	2022-11-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000442571	SCV002071675	benign	not specified	2017-11-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001080850	SCV004017083	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679642	SCV005041866	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	POLE: BP4, BS1, BS2
True Health Diagnostics	RCV000567511	SCV000788183	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356585	SCV001551796	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Ala1712Val variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs5744950) as "With other allele ", ClinVar (classified as benign by Invitae and one clinical laboratory; as likely benign by GeneDx, Ambry Genetics, and two clinical laboratories), and in MutDB, databases. The variant was identified in control databases in 283 of 270890 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 264 of 23978 chromosomes (freq: 0.01), Other in 2 of 6284 chromosomes (freq: 0.0003), Latino in 17 of 33638 chromosomes (freq: 0.0005), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala1712 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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 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.