Submissions for variant NM_002691.4(POLD1):c.518G>A (p.Ser173Asn)

gnomAD frequency: 0.03166  dbSNP: rs1726803

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424652	SCV000518891	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.
Invitae	RCV001084357	SCV000558771	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000424652	SCV000601946	benign	not specified	2016-08-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569972	SCV000670875	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	RCV000586444	SCV000698013	benign	not provided	2016-05-18	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.518G>A (p.Ser173Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 1114/120932 control chromosomes (including 57 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1000194 (1030/10298). This frequency is about 7041 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	RCV000424652	SCV000806546	benign	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000424652	SCV002761045	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001084357	SCV004016623	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000569972	SCV000788150	likely benign	Hereditary cancer-predisposing syndrome	2017-10-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357026	SCV001552350	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Ser173Asn variant was identified in dbSNP (ID: rs1726803) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 2724 (141 homozygous) of 276964 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 2439 (139 homozygous) of 23962 chromosomes (freq: 0.10), Other in 20 of 6462 chromosomes (freq: 0.003), Latino in 231 (2 homozygous) of 34410 chromosomes (freq: 0.007), European Non-Finnish in 31 of 126566 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10142 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.00007), while not observed in the East Asian and European Finnish populations. The p.Ser173 residue is conserved in in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact of Asn to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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	RCV000424652	SCV001808389	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000424652	SCV001923943	benign	not specified		no assertion criteria provided	clinical testing