Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001017711 | SCV001178834 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-26 | criteria provided, single submitter | clinical testing | The c.840+3G>T intronic variant results from a G to T substitution 3 nucleotides after coding exon 6 in the POLD1 gene. This nucleotide position is poorly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to create a new alternate splice acceptor site, but BDGP does not predict the creation of a non-native acceptor site, nor a deleterious effect on splicing. Using the Human Splicing Finder (HSF) splice site prediction tool, this alteration does not have any significant effect on the native splice acceptor/donor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001070765 | SCV001236033 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2024-01-09 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 of the POLD1 gene. It does not directly change the encoded amino acid sequence of the POLD1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). 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: 822387). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. |
| Gene |
RCV001766841 | SCV001999444 | uncertain significance | not provided | 2019-10-21 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |