Submissions for variant NM_006231.4(POLE):c.5570A>G (p.Lys1857Arg)

dbSNP: rs5744971

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679651	SCV000262288	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000237099	SCV000293172	likely benign	not specified	2017-12-13	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	RCV000561298	SCV000671263	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	RCV004529005	SCV000806810	benign	POLE-related disorder	2019-09-04	criteria provided, single submitter	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000237099	SCV000888558	benign	not specified	2017-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000237099	SCV000918083	benign	not specified	2018-07-10	criteria provided, single submitter	clinical testing	Variant summary: POLE c.5570A>G (p.Lys1857Arg) results in a conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.00092 in 277088 control chromosomes (gnomAD). The observed variant frequency within African control individuals in the gnomAD database is approximately 697-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.5570A>G 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	RCV000679651	SCV001157650	likely benign	not provided	2022-11-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000237099	SCV002071558	benign	not specified	2017-11-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561298	SCV002536894	benign	Hereditary cancer-predisposing syndrome	2020-07-02	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002485353	SCV002801289	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	2021-08-25	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001080849	SCV004017082	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679651	SCV005042114	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	POLE: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000679651	SCV005217314	likely benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000561298	SCV000788157	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357564	SCV001553070	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Lys1857Arg variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs5744971) as "With Uncertain significance, 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 256 of 277088 chromosomes at a frequency of 0.0009 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 238 of 24034 chromosomes (freq: 0.01), Other in 2 of 6462 chromosomes (freq: 0.0003), Latino in 15 of 34396 chromosomes (freq: 0.0004), European in 1 of 126646 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys1857 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.