Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000562117 | SCV000674282 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-08 | criteria provided, single submitter | clinical testing | The p.Q165* variant (also known as c.493C>T), located in coding exon 4 of the POLD1 gene, results from a C to T substitution at nucleotide position 493. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of 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. |
| Gene |
RCV000657703 | SCV000779452 | uncertain significance | not provided | 2018-01-26 | criteria provided, single submitter | clinical testing | This variant is denoted POLD1 c.493C>T at the cDNA level and p.Gln165Ter (Q165X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not, to our knowledge, been published in the literature. While some missense variants in POLD1 have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider this variant to be of uncertain significance with respect to cancer. |
| Invitae | RCV001062594 | SCV001227406 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-05-30 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln165*) in 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 not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 486063). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. |