Submissions for variant NM_006231.4(POLE):c.5496T>C (p.Leu1832=)

gnomAD frequency: 0.00029  dbSNP: rs147543146

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000759308	SCV000289424	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000759308	SCV000518252	likely benign	not provided	2021-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568242	SCV000671284	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	RCV000419491	SCV000806805	benign	not specified	2017-08-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000419491	SCV000888555	benign	not specified	2018-07-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759308	SCV001249332	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	POLE: BP4, BP7
Genetic Services Laboratory, University of Chicago	RCV000419491	SCV002066957	likely benign	not specified	2021-06-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568242	SCV002536891	benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000419491	SCV002550061	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000419491	SCV003922982	benign	not specified	2023-03-17	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000568242	SCV000886714	likely benign	Hereditary cancer-predisposing syndrome	2018-10-04	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354374	SCV001548977	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Leu1832= variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs147543146) as "With Likely benign allele", and in ClinVar (classified as benign by Invitae; as likely benign by GeneDx, Ambry Genetics, and one other clinical laboratory). The variant was identified in control databases in 167 of 277186 chromosomes (1 homozygous) at a frequency of 0.0006 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: Other in 2 of 6466 chromosomes (freq: 0.0003), European in 43 of 126684 chromosomes (freq: 0.0003), Ashkenazi Jewish in 40 of 10152 chromosomes (1 homozygous, freq: 0.0039), East Asian in 27 of 18870 chromosomes (freq: 0.0014), Finnish in 25 of 25790 chromosomes (freq: 0.001), and South Asian in 30 of 30782 chromosomes (freq: 0.00097), while the variant was not observed in the African or Latino populations. The p.Leu1832= 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.