ClinVar Miner

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

gnomAD frequency: 0.00103  dbSNP: rs369613619
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000990268 SCV000287611 benign Colorectal cancer, susceptibility to, 10 2021-12-17 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000427254 SCV000601931 likely benign not specified 2017-02-04 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: 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,PreventionGenetics 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 RCV000588808 SCV000889675 benign not provided 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 benign not provided 2022-03-01 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000570956 SCV002534660 likely benign Hereditary cancer-predisposing syndrome 2020-12-03 criteria provided, single submitter curation
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000427254 SCV002551987 likely benign not specified 2021-10-01 no assertion criteria provided clinical testing

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