Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001071391 | SCV001236694 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2019-01-29 | criteria provided, single submitter | clinical testing | Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein, while not abolishing its polymerase enzyme activity, are associated with an increased risk for colonic adenomatous polyps and colon cancer (PMID: 23263490, 23447401). Loss-of-function variants, which result in an absent or severely disrupted POLD1 protein, are therefore unlikely to be associated with disease. Without further clinical and genetic evidence, however, this variant has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with POLD1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys554Thrfs*13) in the POLD1 gene. It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV002402485 | SCV002707538 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-11-16 | criteria provided, single submitter | clinical testing | The c.1661_1670del10 variant, located in coding exon 12 of the POLD1 gene, results from a deletion of 10 nucleotides between nucleotide positions 1661 and 1670, causing a translational frameshift with a predicted alternate stop codon. 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 6503 samples (13006 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. 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). |