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

gnomAD frequency: 0.00167  dbSNP: rs116076060

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589822	SCV000262351	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000589822	SCV000518907	likely benign	not provided	2021-09-07	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	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.
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, part of Exact Sciences	RCV000589822	SCV000806837	likely benign	not provided	2017-06-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000438768	SCV000888564	benign	not specified	2018-06-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589822	SCV001148871	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	POLE: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589822	SCV002049201	likely benign	not provided	2023-10-20	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000438768	SCV002550034	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001081414	SCV004017077	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
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