Submissions for variant NM_002691.4(POLD1):c.3054G>A (p.Val1018=)

gnomAD frequency: 0.00103  dbSNP: rs369613619

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000990268	SCV000287611	benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000588808	SCV000521702	likely benign	not provided	2021-06-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25356899)
Genetic Services Laboratory, University of Chicago	RCV000427254	SCV000596494	likely benign	not specified	2017-05-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570956	SCV000670907	likely benign	Hereditary cancer-predisposing syndrome	2015-07-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000588808	SCV000698003	benign	not provided	2017-05-23	criteria provided, single submitter	clinical testing	Variant summary: The POLD1 c.3054G>A (p.Val1018Val) variant involves the alteration of a non-conserved nucleotide causes a synonymous change and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 89/139890 control chromosomes at a frequency of 0.0006362, which is approximately 45 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000588808	SCV000806520	likely benign	not provided	2017-04-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000588808	SCV000859724	uncertain significance	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000427254	SCV000889675	benign	not specified	2017-08-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000990268	SCV001141163	likely benign	Colorectal cancer, susceptibility to, 10	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588808	SCV001152042	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	POLD1: BP4, BP7, BS1
Sema4, Sema4	RCV000570956	SCV002534660	likely benign	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000427254	SCV002551987	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588808	SCV004564645	likely benign	not provided	2023-10-25	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354929	SCV001549657	likely benign	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLD1 p.Val1018= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs369613619) “With Likely benign allele”, and ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by Invitae and 2 other laboratories, likely benign by GeneDx, Ambry Genetics, Prevention Genetics and 2 other laboratories, and uncertain significance by EGL Genetic Diagnostics (Eurofins Clinical Genetics)).The variant was identified in control databases in 89 of 162606 chromosomes at a frequency of 0.0005 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 3 of 15192 chromosomes (freq: 0.0002), Other in 2 of 4524 chromosomes (freq: 0.0004), Latino in 17 of 24616 chromosomes (freq: 0.0007), European Non-Finnish in 63 of 64570 chromosomes (freq: 0.001), European Finnish in 4 of 11144 chromosomes (freq: 0.0004), while not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The variant was also identified by our laboratory in 1 individual with pancreatic cancer, co-occurring with a pathogenic ATM variant (c.8418+5_8418+8del, r.spl?), increasing the likelihood the variant has little clinical significance. The p.Val1018= 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. 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 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.
Clinical Genetics, Academic Medical Center	RCV000427254	SCV001921828	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588808	SCV001968196	likely benign	not provided		no assertion criteria provided	clinical testing