ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.5570A>G (p.Lys1857Arg) (rs5744971)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080849 SCV000262288 benign Colorectal cancer, susceptibility to, 12 2020-12-01 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000237099 SCV000602070 benign not specified 2017-04-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000561298 SCV000671263 likely benign Hereditary cancer-predisposing syndrome 2015-06-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
PreventionGenetics,PreventionGenetics RCV000679651 SCV000806810 likely benign not provided 2018-01-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679651 SCV000888558 benign not provided 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 RCV001282726 SCV001157650 likely benign none provided 2020-01-05 criteria provided, single submitter clinical testing
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.

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