Submissions for variant NM_002691.4(POLD1):c.2244T>C (p.Ser748=)

gnomAD frequency: 0.10634  dbSNP: rs1274607

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000426269	SCV000518038	benign	not specified	2015-11-06	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.
Invitae	RCV000465977	SCV000558713	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564893	SCV000670880	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: 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	RCV000587842	SCV000697997	benign	not provided	2016-05-19	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.2244T>C (p.Ser748Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 4143/92154 control chromosomes (542 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.3593498 (3117/8674). This frequency is about 25298 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. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000426269	SCV000806495	benign	not specified	2017-03-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000426269	SCV002551953	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000465977	SCV004016618	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357603	SCV001553117	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Ser748= variant was identified in dbSNP (ID: rs1274607) as “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae and Ambry Genetics), and in control databases in 10176 of 264892 chromosomes (1384 homozygous) at a frequency of 0.04 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 7802 (1337 homozygous) of 22948 chromosomes (freq: 0.34), Other in 124 (3 homozygous) of 6258 chromosomes (freq: 0.02), Latino in 670 (13 homozygous) of 33116 chromosomes (freq: 0.02), European Non-Finnish in 216 of 120574 chromosomes (freq: 0.002), Ashkenazi Jewish in 195 (2 homozygous) of 9974 chromosomes (freq: 0.02), East Asian in 21 of 17784 chromosomes (freq: 0.001), and South Asian in 1148 (29 homozygous) of 29792 chromosomes (freq: 0.04), while not observed in the European Finnish population. The p.Ser748Ser 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.
Clinical Genetics, Academic Medical Center	RCV000426269	SCV002034382	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000426269	SCV002035669	benign	not specified		no assertion criteria provided	clinical testing