ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1761C>T (p.Ile587=)

gnomAD frequency: 0.00976  dbSNP: rs3218755
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001084358 SCV000261937 benign Colorectal cancer, susceptibility to, 10 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000437612 SCV000520790 benign not specified 2017-05-25 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 RCV000568794 SCV000670898 benign Hereditary cancer-predisposing syndrome 2015-05-20 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.
PreventionGenetics, part of Exact Sciences RCV000437612 SCV000806476 benign not specified 2017-01-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000437612 SCV000888435 benign not specified 2016-08-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000437612 SCV000920060 benign not specified 2017-10-12 criteria provided, single submitter clinical testing Variant summary: The POLD1 c.1761C>T (p.Ile587Ile) 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 does not alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 868/268896 control chromosomes (gnomAD), predominantly observed in the African subpopulation at a frequency of 0.032564 (753/23124, 13 homozygotes). This frequency is about 2292 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. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000759216 SCV002050084 benign not provided 2023-01-06 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000437612 SCV002761058 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV001084358 SCV004016628 benign Colorectal cancer, susceptibility to, 10 2023-07-07 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000759216 SCV005309863 benign not provided criteria provided, single submitter not provided
True Health Diagnostics RCV000568794 SCV000788133 likely benign Hereditary cancer-predisposing syndrome 2017-10-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355699 SCV001550655 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLD1 p.Ile587= variant was not identified in the literature nor was it identified in Cosmic or MutDB. The variant was identified in dbSNP (ID: rs3218755 as With Likely benign allele) and ClinVar (classified as benign by Invitae, GeneDx, Ambry Genetics and Quest Diagnostics). The variant was also identified in control databases in 868 of 268896 chromosomes (13 homozygous) at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). This variant was observed in the following populations: African in 753 of 23124 chromosomes (freq: 0.03), Other in 10 of 6290 chromosomes (freq: 0.002), Latino in 96 of 33914 chromosomes (freq: 0.003), European Non-Finnish in 8 of 122672 chromosomes (freq: 0.00007), and Ashkenazi Jewish in 1 of 9970 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian, Finnish, or South Asian populations. The p.Ile587= variant is not expected to have clinical significance because it does not result in a change of amino acid and c.1761 is not a well conserved nucleotide. In addition, the variant is not located in a known consensus splice site and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the available information suggests a benign role for this variant. This variant is classified as likely benign.

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