Submissions for variant NM_006231.4(POLE):c.6495C>T (p.Arg2165=)

gnomAD frequency: 0.00053  dbSNP: rs114778730

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679664	SCV000289462	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000679664	SCV000521140	likely benign	not provided	2020-10-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575910	SCV000671254	likely benign	Hereditary cancer-predisposing syndrome	2015-06-22	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	RCV000679664	SCV000806839	likely benign	not provided	2017-04-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679664	SCV000888568	benign	not provided	2018-06-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679664	SCV001473979	likely benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575910	SCV002536917	likely benign	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265704	SCV002548400	benign	not specified	2022-05-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500794	SCV002813720	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	2022-05-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002265704	SCV004027287	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679664	SCV005050919	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	POLE: BP4, BP7
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354477	SCV001549104	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Arg2165= variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs114778730) as "With Likely benign allele" and in ClinVar (classified as benign by Invitae; and as likely benign by GeneDx and Ambry Genetics). The variant was identified in control databases in 169 of 268900 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 23124 chromosomes (freq: 0.0002), Other in 7 of 6322 chromosomes (freq: 0.001), Latino in 18 of 33610 chromosomes (freq: 0.0005), European in 121 of 122322 chromosomes (freq: 0.001), Finnish in 17 of 25164 chromosomes (freq: 0.0007), and South Asian in 2 of 29946 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg2165= 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.