Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000640191 | SCV000761780 | uncertain significance | Oligodontia-cancer predisposition syndrome | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 7 of the AXIN2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with breast or ovarian cancer (PMID: 30322717, 34196900). ClinVar contains an entry for this variant (Variation ID: 533167). Studies have shown that disruption of this splice site results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (Invitae). Tissue-specific alternative splicing of AXIN2 gene results in functional isoform lacking in-frame exon 7, also known as exon 6 (PMID: 15735151). For this reason the clinical significance of loss of exon 7 is currently uncertain. 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. |
| Ambry Genetics | RCV001013645 | SCV001174258 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-13 | criteria provided, single submitter | clinical testing | The c.1908-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 7 in the AXIN2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 3 amino acids; however, the exact functional impact of the deleted amino acids are unknown at this time (Ambry internal data). Another alteration impacting the same acceptor site (c.1908-1G>A) has been shown to have a similar impact on splicing. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV002473083 | SCV002770402 | uncertain significance | not provided | 2022-12-23 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Identified in individuals with ovarian cancer (Carter et al., 2018); This variant is associated with the following publications: (PMID: 15735151, 30322717) |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV002473083 | SCV002774260 | likely pathogenic | not provided | 2021-08-02 | criteria provided, single submitter | clinical testing | This variant is located in a canonical splice-acceptor site and is predicted to interfere with normal AXIN2 mRNA splicing. The variant has been reported in an individual affected with ovarian cancer in the published literature (PMID: 30322717 (2018)). Based on the available information, this variant is classified as likely pathogenic. |
| Baylor Genetics | RCV003472014 | SCV004213067 | uncertain significance | Colorectal cancer | 2023-08-06 | criteria provided, single submitter | clinical testing |