Submissions for variant NM_006231.4(POLE):c.4941C>T (p.Phe1647=)

gnomAD frequency: 0.00027  dbSNP: rs145639967

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679640	SCV000521428	likely benign	not provided	2021-10-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679640	SCV000556293	benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566697	SCV000671353	likely benign	Hereditary cancer-predisposing syndrome	2015-06-28	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.
PreventionGenetics, part of Exact Sciences	RCV000679640	SCV000806792	likely benign	not provided	2017-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679640	SCV000889762	benign	not provided	2018-03-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679640	SCV001148882	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	POLE: BP4, BP7
Sema4, Sema4	RCV000566697	SCV002536870	likely benign	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001079709	SCV004017057	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596179	SCV005090440	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000679640	SCV005217321	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679640	SCV001550019	likely benign	not provided		no assertion criteria provided	clinical testing	The POLE p.Phe1647= variant was not identified in the literature nor was it identified in the Cosmic, or MutDB, databases. The variant was identified in dbSNP (ID: rs145639967) as "With Likely benign allele", and in ClinVar database (classified as benign by Invitae; as likely benign by GeneDx, Ambry Genetics and Prevention Genetics). The variant was identified in control databases in 60 of 276406 chromosomes at a frequency of 0.0002 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 20 of 23994 chromosomes (freq: 0.0008), Other in 2 of 6460 chromosomes (freq: 0.0003), European in 1 of 126126 chromosomes (freq: 0.000008), East Asian in 30 of 18860 chromosomes (freq: 0.002), and South Asian in 7 of 30774 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, and Finnish, populations. The p.Phe1647= 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, HumanSpliceFinder) 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.