Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000687108 | SCV000814660 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2021-04-18 | criteria provided, single submitter | clinical testing | Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1/POLE 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 truncating variants, which result in an absent or severely disrupted POLD1/POLE 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 disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr809*) in the POLD1 gene. It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV001015494 | SCV001176333 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-30 | criteria provided, single submitter | clinical testing | The p.Y809* variant (also known as c.2427C>A), located in coding exon 19 of the POLD1 gene, results from a C to A substitution at nucleotide position 2427. This changes the amino acid from a tyrosine to a stop codon within coding exon 19. This alteration is expected to result in loss of function by premature protein truncation or 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. |