ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.5135C>T (p.Ala1712Val) (rs5744950)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080850 SCV000262287 benign Colorectal cancer, susceptibility to, 12 2020-12-01 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000442571 SCV000602062 benign not specified 2017-04-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567511 SCV000671264 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 RCV000679642 SCV000806796 likely benign not provided 2018-01-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679642 SCV000889768 benign not provided 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 RCV001282210 SCV001157648 likely benign none provided 2020-01-05 criteria provided, single submitter clinical testing
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.

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