Submissions for variant NM_002691.4(POLD1):c.1977C>T (p.Ile659=)

gnomAD frequency: 0.00290  dbSNP: rs45605236

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205393	SCV000262395	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000423569	SCV000518487	benign	not specified	2016-05-25	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.
Genetic Services Laboratory, University of Chicago	RCV000423569	SCV000596493	benign	not specified	2021-05-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566611	SCV000670886	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	RCV000587636	SCV000697994	benign	not provided	2016-08-26	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.1977C>T (p.Ile659Ile) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 288/119080 control chromosomes (1 homozygote) at a frequency of 0.0024185, which is approximately 170 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory in ClinVar has classified this variant as benign. The variant of interest has not been reported in affected individuals via publications, to our knowledge. Taken together, this variant is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000423569	SCV000806482	benign	not specified	2016-12-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000423569	SCV000860264	benign	not specified	2018-04-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000423569	SCV000888444	benign	not specified	2016-12-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587636	SCV001152030	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	POLD1: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587636	SCV002049673	benign	not provided	2023-10-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566611	SCV002534613	benign	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000423569	SCV002551942	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000205393	SCV000733914	likely benign	Colorectal cancer, susceptibility to, 10		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000566611	SCV000788122	likely benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357835	SCV001553422	likely benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLD1 p.Ile659= variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs45605236) “With other allele”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano, and likely benign by Genetic Services Laboratory (University of Chicago)), Clinvitae (3x), and in control databases in 683 (1 homozygous) of 276786 chromosomes at a frequency of 0.002 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 25 of 23988 chromosomes (freq: 0.001), Other in 13 of 6462 chromosomes (freq: 0.002), Latino in 127 (1 homozygous) of 34414 chromosomes (freq: 0.004), European Non-Finnish in 481 of 126400 chromosomes (freq: 0.004), Ashkenazi Jewish in 24 of 10134 chromosomes (freq: 0.002), European Finnish in 12 of 25748 chromosomes (freq: 0.0005), and South Asian in 1 of 30776 chromosomes (freq: 0.00003) while not observed in the East Asian population. The p.Ile659= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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	RCV000423569	SCV001807006	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000423569	SCV001917259	benign	not specified		no assertion criteria provided	clinical testing