ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.590-2A>G

gnomAD frequency: 0.00001  dbSNP: rs758877520
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409655 SCV000489449 uncertain significance Colorectal cancer, susceptibility to, 10 2016-10-11 criteria provided, single submitter clinical testing
Invitae RCV000409655 SCV000547422 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with PPAP (polymerase proofreading–associated polyposis) (PMID: 23263490, 23447401). However, loss-of-function variants that result in an absent or severely disrupted POLD1 protein, and missense variants outside the exonuclease domain, are unlikely to be associated with PPAP. This variant is present in population databases (rs758877520, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 372001). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000567823 SCV000671144 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-29 criteria provided, single submitter clinical testing The c.590-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the POLD1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function via haploinsufficiency in POLD1 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001546219 SCV001765700 uncertain significance not provided 2020-08-14 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele, but clinical significance is uncertain; Some missense variants in POLD1 have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP); however, there are no data at this time to support that loss-of-function variants confer the same cancer risks; Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002488845 SCV002783213 uncertain significance Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome 2021-08-20 criteria provided, single submitter clinical testing

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