Submissions for variant NM_002691.4(POLD1):c.1713C>T (p.Pro571=)

gnomAD frequency: 0.01698  dbSNP: rs2230248

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079260	SCV000287533	benign	Colorectal cancer, susceptibility to, 10	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000442456	SCV000518037	benign	not specified	2015-11-11	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.
Ambry Genetics	RCV000569786	SCV000670881	benign	Hereditary cancer-predisposing syndrome	2015-05-21	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.
PreventionGenetics, part of Exact Sciences	RCV000442456	SCV000806474	benign	not specified	2016-12-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000442456	SCV000888434	benign	not specified	2016-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442456	SCV000920059	benign	not specified	2017-10-12	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.1713C>T (p.Pro571Pro) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1443/274898 control chromosomes (gnomAD), predominantly observed in the African subpopulation at a frequency of 0.053441 (1269/23746, 32 homozygotes). This frequency is about 3762 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000442456	SCV002551931	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001079260	SCV004016636	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736656	SCV004564927	benign	not provided	2024-10-18	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV003736656	SCV005309862	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000569786	SCV000788132	likely benign	Hereditary cancer-predisposing syndrome	2018-01-03	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354870	SCV001549586	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Pro571= variant was identified in dbSNP (ID: rs2230248) “With Benign allele”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 1443 (33 homozygous) of 274898 chromosomes at a frequency of 0.005 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 1269 (32 homozygous) of 23746 chromosomes (freq: 0.05), Other in 26 of 6408 chromosomes (freq: 0.004), Latino in 104 (1 homozygous) of 34354 chromosomes (freq: 0.003), European Non-Finnish in 30 of 125554 chromosomes (freq: 0.0002), Ashkenazi Jewish in 8 of 10100 chromosomes (freq: 0.0008), East Asian in 1 of 18828 chromosomes (freq: 0.00005), and South Asian in 5 of 30682 chromosomes (freq: 0.0002) while not observed in the European Finnish population. The p.Pro571= 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.