Submissions for variant NM_002691.4(POLD1):c.2628C>T (p.Ile876=)

gnomAD frequency: 0.00088  dbSNP: rs75874199

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083156	SCV000261467	benign	Colorectal cancer, susceptibility to, 10	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000419687	SCV000518255	benign	not specified	2015-11-18	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	RCV000560967	SCV000670891	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: 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	RCV000589705	SCV000698001	benign	not provided	2017-07-28	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.2628C>T (p.Ile876Ile) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant alters binding of SRp55 and SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 271/116036 control chromosomes (3 homozygotes) at a frequency of 0.0023355, which is approximately 164 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. It is more common in East Asian subpopulation with an allele frequency of 0.0293 (248/8464 chromosomes). In addition, multiple clinical diagnostic laboratories 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	RCV000419687	SCV000806507	benign	not specified	2017-03-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000419687	SCV000889672	benign	not specified	2016-07-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000560967	SCV002534641	benign	Hereditary cancer-predisposing syndrome	2021-05-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000419687	SCV002761075	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589705	SCV003800262	benign	not provided	2022-06-22	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001083156	SCV004016662	benign	Colorectal cancer, susceptibility to, 10	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000589705	SCV005309873	benign	not provided		criteria provided, single submitter	not provided
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000560967	SCV005688939	benign	Hereditary cancer-predisposing syndrome	2025-01-15	criteria provided, single submitter	clinical testing	The synonymous variant NM_001308632.1(POLD1):c.2706C>T (p.Ile902=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 220703 as of 2025-01-02). The p.Ile902= variant is not predicted to disrupt an existing splice site. The p.Ile902= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign.
True Health Diagnostics	RCV000560967	SCV000788142	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000419687	SCV001552076	benign	not specified		no assertion criteria provided	clinical testing	The POLD1 p.Ile876= variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs75874199) as "With Benign allele ", and in ClinVar database (classified as benign by Invitae, GeneDx, Ambry Genetics, and three clinical laboratories; as likely benign by one clinical laboratory). The variant was identified in control databases in 662 of 275698 chromosomes (12 homozygous) at a frequency of 0.002 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 4 of 23876 chromosomes (freq: 0.0002), Other in 8 of 6434 chromosomes (freq: 0.001), Latino in 3 of 34348 chromosomes (freq: 0.00009), European in 6 of 125698 chromosomes (freq: 0.00005), East Asian in 608 of 18808 chromosomes (freq: 0.03), and South Asian in 33 of 30756 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish, and Finnish, populations. The p.Ile876= 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) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.