ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6453C>T (p.Tyr2151=)

gnomAD frequency: 0.00167  dbSNP: rs116076060
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081414 SCV000262351 benign Colorectal cancer, susceptibility to, 12 2021-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000589822 SCV000518907 likely benign not provided 2021-09-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000438768 SCV000602082 likely benign not specified 2017-02-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562702 SCV000671266 likely benign Hereditary cancer-predisposing syndrome 2015-06-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Synonymous alterations with insufficient evidence to classify as benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589822 SCV000698685 benign not provided 2016-08-17 criteria provided, single submitter clinical testing Variant summary: The POLE c.6453C>T (p.Tyr2151Tyr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 268/109324 control chromosomes at a frequency of 0.0024514, which is approximately 173 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000589822 SCV000806837 likely benign not provided 2017-06-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589822 SCV000888564 benign not provided 2018-06-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589822 SCV002049201 likely benign not provided 2021-11-24 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000438768 SCV002065126 likely benign not specified 2021-01-07 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000562702 SCV002536914 benign Hereditary cancer-predisposing syndrome 2020-07-08 criteria provided, single submitter curation
True Health Diagnostics RCV000562702 SCV000805304 likely benign Hereditary cancer-predisposing syndrome 2018-05-21 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357618 SCV001553139 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLE p.Tyr2151= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs116076060) as "With Likely benign allele", and in ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Ambry Genetics and three other submitters). The variant was identified in control databases in 481 of 276354 chromosomes (1 homozygous) at a frequency of 0.002 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 9 of 23940 chromosomes (freq: 0.0004), Other in 11 of 6448 chromosomes (freq: 0.002), Latino in 17 of 34362 chromosomes (freq: 0.0005), European in 372 of 126202 chromosomes (freq: 0.003), Finnish in 72 of 25708 chromosomes (freq: 0.003), while the variant was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Tyr2151= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000589822 SCV001808593 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000438768 SCV001921660 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000589822 SCV001971209 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000438768 SCV002550034 likely benign not specified 2021-09-21 no assertion criteria provided clinical testing

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