Submissions for variant NM_002691.4(POLD1):c.88C>T (p.Arg30Trp)

gnomAD frequency: 0.00706  dbSNP: rs3218772

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204228	SCV000262391	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000204228	SCV000488499	benign	Colorectal cancer, susceptibility to, 10	2016-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000420692	SCV000517983	benign	not specified	2016-11-17	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	RCV000576004	SCV000670882	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	RCV000588327	SCV000698017	benign	not provided	2016-08-25	criteria provided, single submitter	clinical testing	Variant summary: The c.88C>T (p.Arg30Trp) in POLD1 gene is a missense change that involves a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.013 (671/52972 chrs tested) including 5 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant was identified in a clinical case, which also carried a known pathogenic mutation, c.68_69delAG, in BRCA1 gene. The variant is cited as Benign by a reputable database/clinical laboratory. Taking together, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000420692	SCV000806568	benign	not specified	2016-12-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000420692	SCV000889699	benign	not specified	2016-07-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588327	SCV001157561	benign	not provided	2023-09-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000420692	SCV002552079	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588327	SCV002563542	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	POLD1: BP4, BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV002500664	SCV002807079	likely benign	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2022-03-16	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204228	SCV004016621	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000576004	SCV000788155	likely benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588327	SCV001552549	likely benign	not provided		no assertion criteria provided	clinical testing	The POLD1 p.Arg30Trp variant was identified in 1 of 58 proband chromosomes (frequency: 0.02) from individuals or families with HNPCC (Talseth-Palmer 2015). The variant was also identified in dbSNP (ID: rs3218772) as "With Benign allele", ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics and three other clinical laboratories), Cosmic (1x in prostate tissue), and MutDB. The variant was identified in control databases in 1935 of 241054 chromosomes (13 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1228 of 108476 chromosomes (freq: 0.01), South Asian in 299 of 26820 chromosomes (freq: 0.01), African in 28 of 21060 chromosomes (freq: 0.001), Other in 62 of 5816 chromosomes (freq: 0.01), Latino in 183 of 30048 chromosomes (freq: 0.006), Ashkenazi Jewish in 74 of 9266 chromosomes (freq: 0.0079), and Finnish in 61 of 22694 chromosomes (freq: 0.0026), while the variant was not observed in the East Asian population. The p.Arg30 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000588327	SCV001800303	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000420692	SCV001809052	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000420692	SCV001925200	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000420692	SCV001977649	benign	not specified		no assertion criteria provided	clinical testing