ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6763A>T (p.Ile2255Phe)

gnomAD frequency: 0.00845  dbSNP: rs73155056
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206490 SCV000262427 benign Colorectal cancer, susceptibility to, 12 2021-12-18 criteria provided, single submitter clinical testing
Counsyl RCV000206490 SCV000488480 likely benign Colorectal cancer, susceptibility to, 12 2016-06-07 criteria provided, single submitter clinical testing
GeneDx RCV000441299 SCV000518048 benign not specified 2017-05-25 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 RCV000492710 SCV000581388 benign Hereditary cancer-predisposing syndrome 2015-06-05 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000441299 SCV000602089 likely benign not specified 2017-02-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000441299 SCV000806848 benign not specified 2016-12-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759321 SCV000888576 benign not provided 2018-03-14 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000759321 SCV001148864 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000759321 SCV001472538 benign not provided 2021-05-08 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000441299 SCV002065093 benign not specified 2017-08-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000441299 SCV002548405 likely benign not specified 2022-05-12 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000492710 SCV000788192 likely benign Hereditary cancer-predisposing syndrome 2017-11-10 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000441299 SCV001551332 benign not specified no assertion criteria provided clinical testing The POLE p.Ile2255Phe variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs73155056) “With Uncertain significance, other allele” and ClinVar (classified benign by Invitae and Ambry Genetics; and as likely benign by Counsyl, GeneDx, and Quest Diagnostics Nichols Insitute San Juan Capistrano). The variant was identified in control databases in 1455 (13 homozygous) of 276312 chromosomes at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Finnish in 687 (12 homozygous) of 25786 chromosomes (freq: 0.03), African in 21 of 24016 chromosomes (freq: 0.0009), Other in 40 of 6460 chromosomes (freq: 0.006), Latino in 56 (1 homozygous) of 34420 chromosomes (freq: 0.002), European Non-Finnish in 612 of 125828 chromosomes (freq: 0.005), Ashkenazi Jewish in 22 of 10152 chromosomes (freq: 0.002), and South Asian in 17 of 30782 chromosomes (freq: 0.0006); it was not observed in the East Asian population. The p.Ile2255 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 the variant Phe impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000759321 SCV001742187 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000441299 SCV001807763 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000759321 SCV001920061 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000759321 SCV001970673 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000441299 SCV002550016 likely benign not specified 2021-09-21 no assertion criteria provided clinical testing

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