Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000569535 | SCV000671107 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-01-06 | criteria provided, single submitter | clinical testing | The c.2954-2delA intronic variant, results from a deletion of one nucleotide two nucleotides upstream from coding exon 23 of the POLD1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6411 samples (12822 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 25000 alleles tested) in our clinical cohort. 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. As neither this specific alteration nor loss of function as a mechanism of pathogenicity have been well-described in the POLD1 gene, the clinical significance of this variant remains unknown (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015 May; 17(5):405-23). |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759236 | SCV000888460 | uncertain significance | not provided | 2018-04-17 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003640911 | SCV004462535 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-05-08 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with POLD1-related conditions. 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. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). ClinVar contains an entry for this variant (Variation ID: 484362). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 23 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. |