Submissions for variant NM_002691.4(POLD1):c.1173C>T (p.Asp391=)

gnomAD frequency: 0.02764  dbSNP: rs2230244

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436068	SCV000519087	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	RCV001079838	SCV000558766	benign	Colorectal cancer, susceptibility to, 10	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571194	SCV000670884	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	RCV000588381	SCV000697989	benign	not provided	2016-08-26	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.1173C>T (p.Asp391Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 999/121398 control chromosomes (42 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0874495 (910/10406). This frequency is about 6156 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 origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000436068	SCV000806459	benign	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000436068	SCV000888432	benign	not specified	2020-08-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000436068	SCV002551906	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588381	SCV003799432	benign	not provided	2023-10-20	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001079838	SCV004016625	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000588381	SCV005309852	benign	not provided		criteria provided, single submitter	not provided
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000571194	SCV005688954	benign	Hereditary cancer-predisposing syndrome	2025-01-20	criteria provided, single submitter	clinical testing	The synonymous variant NM_001308632.1(POLD1):c.1173C>T (p.Asp391=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380706 as of 2025-01-02). The variant is observed in one or more well-documented healthy adults. All background in 1kG, indicating it is a common benign variant. The p.Asp391= variant is not predicted to disrupt an existing splice site. The p.Asp391= 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	RCV000571194	SCV000788125	likely benign	Hereditary cancer-predisposing syndrome	2017-10-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357635	SCV001553160	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Asp391= variant was identified in dbSNP (ID: rs2230244) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 2422 (97 homozygous) of 277198 chromosomes at a frequency of 0.009 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 2125 (97 homozygous) of 24026 chromosomes (freq: 0.09), Other in 25 of 6466 chromosomes (freq: 0.004), Latino in 230 of 34420 chromosomes (freq: 0.007), European Non-Finnish in 39 of 126692 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), European Finnish in 1 of 25792 chromosomes (freq: 0.00004), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while not observed in the East Asian population. The p.Asp391= 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	RCV000436068	SCV001808007	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000436068	SCV001925487	benign	not specified		no assertion criteria provided	clinical testing