Submissions for variant NM_002691.4(POLD1):c.849G>T (p.Gln283His)

gnomAD frequency: 0.01085  dbSNP: rs113282414

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203707	SCV000261456	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000203707	SCV000488605	benign	Colorectal cancer, susceptibility to, 10	2016-05-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000586017	SCV000518482	benign	not provided	2018-05-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26249178)
Ambry Genetics	RCV000561488	SCV000670888	benign	Hereditary cancer-predisposing syndrome	2015-05-21	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	RCV000586017	SCV000698016	benign	not provided	2016-08-26	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.849G>T (p.Gln283His) variant involves the alteration of a non-conserved nucleotide located at ribonuclease H-like domain of the protein (InterPro). 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 197/33948 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.048913 (189/3864). This frequency is about 3443 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a common benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory has classified this variant as benign. 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	RCV000430306	SCV000806563	benign	not specified	2016-10-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000430306	SCV000889697	benign	not specified	2021-10-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586017	SCV001472894	benign	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000430306	SCV002761049	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000203707	SCV004016639	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000203707	SCV004018505	likely benign	Colorectal cancer, susceptibility to, 10	2023-04-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
True Health Diagnostics	RCV000561488	SCV000788154	likely benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358262	SCV001553944	benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	POLD1, EXON8, c.849G>T, p.Gln283His, Heterozygous, BenignrnThe POLD1 p.Gln283His variant was not identified in the literature. The variant was identified in dbSNP (ID: rs113282414) as "With other allele", and in ClinVar (classified as benign by Invitae, Counsyl, Ambry Genetics and four other submitters; as likely benign by two submitters). The variant was identified in control databases in 787 of 211816 chromosomes (15 homozygous) at a frequency of 0.004 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: African in 713 of 18876 chromosomes (freq: 0.04), Other in 7 of 5358 chromosomes (freq: 0.001), Latino in 59 of 26974 chromosomes (freq: 0.002), European in 8 of 91128 chromosomes (freq: 0.00009); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln283 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 this variant meets our laboratory's criteria to be classified as benign.rnAssessment Date: 2019/05/24
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000430306	SCV001809141	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000430306	SCV001954708	benign	not specified		no assertion criteria provided	clinical testing