Submissions for variant NM_002691.4(POLD1):c.1539G>A (p.Leu513=)

gnomAD frequency: 0.04513  dbSNP: rs2230246

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000445323	SCV000518893	benign	not specified	2015-11-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456915	SCV000558772	benign	Colorectal cancer, susceptibility to, 10	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563506	SCV000670877	benign	Hereditary cancer-predisposing syndrome	2015-05-20	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000587462	SCV000697991	benign	not provided	2016-05-18	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.1539G>A (p.Leu513Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1638/120246 control chromosomes (including 116 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1437984 (1484/10320). This frequency is about 10123 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is a common benign polymorphism found primarily in the populations of African. Taken together, this variant is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000445323	SCV000806466	benign	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000445323	SCV000889649	benign	not specified	2020-08-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000445323	SCV002551917	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000456915	SCV004016626	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000587462	SCV005309858	benign	not provided		criteria provided, single submitter	not provided
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000563506	SCV005688955	benign	Hereditary cancer-predisposing syndrome	2025-01-20	criteria provided, single submitter	clinical testing	The synonymous variant NM_001308632.1(POLD1):c.1539G>A (p.Leu513=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380636 as of 2025-01-02). The p.Leu513= variant is observed in 238/5,008 (4.7524%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The p.Leu513= variant is not predicted to disrupt an existing splice site. The p.Leu513= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign
True Health Diagnostics	RCV000563506	SCV000788128	likely benign	Hereditary cancer-predisposing syndrome	2017-10-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358127	SCV001553782	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Leu513= variant was identified in dbSNP (ID: rs2230246) “With Benign allele”, and in control databases in 3896 (256 homozygous) of 276006 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3409 (250 homozygous) of 23968 chromosomes (freq: 0.14), Other in 42 of 6446 chromosomes (freq: 0.007), Latino in 328 (5 homozygous) of 34406 chromosomes (freq: 0.01), European Non-Finnish in 76 (1 homozygous) of 125746 chromosomes (freq: 0.0006), Ashkenazi Jewish in 32 of 10128 chromosomes (freq: 0.003), and South Asian in 9 of 30774 chromosomes (freq: 0.0003), while not observed in the East Asian and European Finnish populations. The p.Leu513= 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 this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000445323	SCV001807187	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000445323	SCV001918428	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000445323	SCV001959290	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000445323	SCV002035926	benign	not specified		no assertion criteria provided	clinical testing