Submissions for variant NM_002691.4(POLD1):c.2154+13_2154+14insA

gnomAD frequency: 0.02057  dbSNP: rs3218767

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586118	SCV000567936	benign	not provided	2019-11-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586118	SCV000697996	benign	not provided	2016-05-19	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.2154+13_2154+14insA variant involves the insertion of an intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 686/112178 control chromosomes (26 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0667447 (627/9394). This frequency is about 4699 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000484350	SCV000806492	benign	not specified	2016-12-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001512798	SCV001720262	benign	Colorectal cancer, susceptibility to, 10	2025-02-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586118	SCV002058069	benign	not provided	2023-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431399	SCV002727216	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000484350	SCV002761062	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355631	SCV001550568	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 c.2154+13_2154+14insA variant was not identified in the literature nor was it identified in MutDB. The variant was identified in dbSNP (ID: rs3218767 as With Benign allele) and ClinVar (2x as benign). The variant was identified in control databases in 1751 of 261160 chromosomes (64 homozygous) at a frequency of 0.007 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 1563 of 23566 chromosomes (freq: 0.07), Latino in 153 of 32366 chromosomes (freq: 0.005), Other in 13 of 6046 chromosomes (freq: 0.002), European Non-Finnish in 20 of 118628 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 8814 chromosomes (freq: 0.0001), South Asian in 1 of 28168 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian or Finnish populations. The variant occurs outside of the splicing consensus sequence and 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 this variant meets our laboratory's criteria to be classified as benign.