Submissions for variant NM_002691.4(POLD1):c.2546G>A (p.Arg849His)

gnomAD frequency: 0.00670  dbSNP: rs3218775

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204415	SCV000261753	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000204415	SCV000488547	benign	Colorectal cancer, susceptibility to, 10	2016-06-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000419079	SCV000518023	benign	not specified	2017-05-09	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	RCV000562311	SCV000670885	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	RCV000586316	SCV000697999	benign	not provided	2016-08-25	criteria provided, single submitter	clinical testing	Variant summary: The c.2546G>A (p.Arg849His) in POLD1 gene is a missense change that involves a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.01 (728/69008 chrs tested) including 4 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant is cited as Benign/Polymorphism by a reputable database/clinical laboratory and published report. Taking together, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000419079	SCV000806503	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000419079	SCV000889668	benign	not specified	2016-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586316	SCV001477656	benign	not provided	2023-09-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562311	SCV002534637	benign	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000419079	SCV002551964	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586316	SCV002585757	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	POLD1: BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV002503812	SCV002803786	likely benign	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2021-10-11	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204415	SCV004016616	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000586316	SCV005309870	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000562311	SCV000788141	benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356421	SCV001551583	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Arg849His variant was identified in 2 of 58 proband chromosomes (frequency: 0.03) from individuals or families with colorectal cancer (Talseth-Palmer 2016). The variant was also identified in dbSNP (ID: rs3218775 as With Likely benign allele), ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and two other clinical laboratories), and LOVD 3.0 (classified as benign and likely benign). The variant was not identified in Cosmic, or MutDB. The variant was identified in control databases in 1854 of 245284 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). This variant was seen in the following populations: African in 27 of 21986 chromosomes (freq: 0.001), Other in 63 of 5744 chromosomes (freq: 0.01), Latino in 209 of 30752 chromosomes (freq: 0.01), European Non-Finnish in 954 of 110672 chromosomes (freq: 0.01), Ashkenazi Jewish in 383 of 9020 chromosomes (freq: 0.04), European Finnish in 174 of 22218 chromosomes (freq: 0.01), and South Asian in 44 of 28122 chromosomes (freq: 0.002); it was not observed in the East Asian population. The p.Arg849 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the available information suggests a benign role. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586316	SCV001806823	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000419079	SCV001922573	benign	not specified		no assertion criteria provided	clinical testing