ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2007-4G>A

gnomAD frequency: 0.00135  dbSNP: rs202035484
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000202855 SCV000257855 benign not specified 2015-07-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000206033 SCV000261396 benign Colorectal cancer, susceptibility to, 10 2024-02-01 criteria provided, single submitter clinical testing
Counsyl RCV000206033 SCV000489206 likely benign Colorectal cancer, susceptibility to, 10 2016-09-02 criteria provided, single submitter clinical testing
GeneDx RCV000202855 SCV000520746 likely benign not specified 2017-12-20 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 RCV000570573 SCV000670910 likely benign Hereditary cancer-predisposing syndrome 2018-06-28 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 RCV000589356 SCV000697995 benign not provided 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The POLD1 c.2007-4G>A variant involves the alteration of a non-conserved 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 151/120110 control chromosomes (1 homozygote) at a frequency of 0.0012572, which is approximately 89 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202855 SCV000888446 benign not specified 2018-04-27 criteria provided, single submitter clinical testing
Mendelics RCV000206033 SCV001141150 likely benign Colorectal cancer, susceptibility to, 10 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000589356 SCV001502264 likely benign not provided 2024-08-01 criteria provided, single submitter clinical testing POLD1: BP4, BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000589356 SCV002047969 benign not provided 2022-09-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000202855 SCV002065992 benign not specified 2017-08-29 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000570573 SCV002534615 benign Hereditary cancer-predisposing syndrome 2020-07-28 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000202855 SCV002551944 likely benign not specified 2023-08-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004737322 SCV000806483 likely benign POLD1-related disorder 2024-05-01 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357515 SCV001553005 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLD1 c.2007-4G>A variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs202035484 as "With Likely benign, Uncertain significance, other allele"), ClinVar (3x as benign by Invitae, and two other clinical laboratories and 4x as likely benign by Counsyl, GeneDx, Ambry Genetics and one other clinical laboratory), and in LOVD 3.0 (2x as benign). The variant was identified in control databases in 346 of 275244 chromosomes (1 homozygous) at a frequency of 0.001, 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 9 of 23976 chromosomes (freq: 0.0004), Other in 5 of 6442 chromosomes (freq: 0.0008), Latino in 37 of 34414 chromosomes (freq: 0.001), European in 237 of 124870 chromosomes (freq: 0.002), Ashkenazi Jewish in 2 of 10138 chromosomes (freq: 0.0002), Finnish in 48 of 25786 chromosomes (freq: 0.002), and South Asian in 8 of 30782 chromosomes (freq: 0.0003); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and 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 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 RCV000202855 SCV001807599 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000202855 SCV001918170 benign not specified no assertion criteria provided clinical testing

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