Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000528286 | SCV000629763 | likely pathogenic | Li-Fraumeni syndrome | 2017-02-15 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 10-11 of the TP53 gene. The 5' boundary is likely confined to intron 9. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Gross deletions encompassing exons 10-11 have been reported in an individual affected with breast cancer and sarcoma (PMID: 21761402) as well as in an individual affected with childhood cancer (PMID: 21056402). This variant has been described in the literature as a deletion of chr. 17:7,511,866 - 7,516,100, relative to the NCBI36/hg18 human genome assembly. While this variant is not anticipated to result in nonsense mediated decay, it is expected to delete the last 62 amino acids of the TP53 protein (Ile332-Asp393). This will result in the loss of most of the tetramerization domain (amino acid residues 320-356), and the complete loss of the C-terminal regulatory region (residues 363-393) (PMID: 20932800, 26205489, 7936651). However, functional studies have not been done to show the impact of these lost amino acids on TP53 protein function. In summary, this variant is a rare gross deletion that is expected to disrupt a functionally important domain of the TP53 protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |