Submissions for variant NM_006231.4(POLE):c.5124C>T (p.Phe1708=)

gnomAD frequency: 0.00149  dbSNP: rs114891564

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760023	SCV000289414	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000760023	SCV000520986	likely benign	not provided	2021-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566689	SCV000671244	likely benign	Hereditary cancer-predisposing syndrome	2015-07-07	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	RCV000422794	SCV000806795	benign	not specified	2018-01-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000422794	SCV000889766	benign	not specified	2018-04-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000422794	SCV002066583	likely benign	not specified	2019-01-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566689	SCV002536877	likely benign	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000422794	SCV002598835	benign	not specified	2022-09-25	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000422794	SCV002760613	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500793	SCV002804194	likely benign	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2022-04-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001080244	SCV004017080	benign	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000760023	SCV005217318	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356677	SCV001551913	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Phe1708= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs114891564) as "With Likely benign allele", in ClinVar (classified 3x as likely benign by GeneDx, Ambry Genetics and one other submitter, 3x benign by Invitae and two other submitters). It was also identified in control databases in 122 of 272712 chromosomes at a frequency of 0.0004 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 116 of 23992 chromosomes (freq: 0.005), Latino in 2 of 33848 chromosomes (freq: 0.00006), European in 2 of 124612 chromosomes (freq: 0.00002), and South Asian in 2 of 29800 chromosomes (freq: 0.00007), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian or Finnish populations. The p.Phe1708= 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.