Submissions for variant NM_002691.4(POLD1):c.56G>A (p.Arg19His)

gnomAD frequency: 0.00197  dbSNP: rs3218773

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204841	SCV000262176	benign	Colorectal cancer, susceptibility to, 10	2025-02-04	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000210816	SCV000267078	likely benign	Hereditary cancer-predisposing syndrome	2015-12-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000204841	SCV000488720	benign	Colorectal cancer, susceptibility to, 10	2016-07-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000419509	SCV000518899	benign	not specified	2017-07-13	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.
Ambry Genetics	RCV000210816	SCV000670897	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	RCV000589239	SCV000698015	benign	not provided	2017-07-21	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.56G>A (p.Arg19His) variant involves the alteration of a non-conserved nucleotide. This variant is located in the nuclear localization signal domain and 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index), however no functional studies supporting these predictions were published at the time of evaluation. This variant was found in 434/63048 control chromosomes (6 homozygotes), observed at relatively higher frequency in the East Asian subpopulation at a frequency of 0.0458626 (235/5124). This frequency is about 3229 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories have classified this variant as likely benign/benign. Lastly, the variant was identified internally in one individual with personal and family history of FAP, who tested positive for a pathogenic variant, c.2161_2170delGGAAGTGCTG in APC gene. Taken together, this variant is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000419509	SCV000806550	benign	not specified	2016-12-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000419509	SCV000888470	benign	not specified	2017-06-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589239	SCV001159158	benign	not provided	2024-02-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000419509	SCV002065980	benign	not specified	2017-08-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000210816	SCV002534688	benign	Hereditary cancer-predisposing syndrome	2020-07-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000419509	SCV002552077	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500662	SCV002807567	likely benign	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome	2021-09-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589239	SCV004140548	benign	not provided	2024-12-01	criteria provided, single submitter	clinical testing	POLD1: BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000589239	SCV005205876	likely benign	not provided		criteria provided, single submitter	not provided
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204841	SCV005881060	benign	Colorectal cancer, susceptibility to, 10	2025-02-01	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000210816	SCV000805292	likely benign	Hereditary cancer-predisposing syndrome	2018-05-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357701	SCV001553249	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The POLD1 p.Arg19His variant was identified in 6 of 152 proband chromosomes (frequency: 0.04) from individuals or families with HNPCC and endometrioid endometrial carcinomas (Talseth-Palmer 2015, Wong 2016 ). The variant was also identified in dbSNP (ID: rs3218773) as With Likely benign allele, ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and two clinical laboratories; as likely benign by Vantari Genetics), Clinvitae, and MutDB databases. The variant was identified in control databases in 1238 of 252406 chromosomes (18 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 19 of 21738 chromosomes (freq: 0.001), Other in 24 of 5994 chromosomes (freq: 0.004), Latino in 520 of 31786 chromosomes (freq: 0.02), European in 26 of 114472 chromosomes (freq: 0.0002), Ashkenazi Jewish in 28 of 9430 chromosomes (freq: 0.003), East Asian in 604 of 17564 chromosomes (freq: 0.03), and South Asian in 17 of 27984 chromosomes (freq: 0.001); but not in the Finnish population. The p.Arg19 residue is not conserved in mammals and four out of five 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 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 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000419509	SCV001808943	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000419509	SCV001921699	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000419509	SCV001970446	benign	not specified		no assertion criteria provided	clinical testing