Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Myriad Genetics, |
RCV005421799 | SCV006091390 | likely pathogenic | Li-Fraumeni syndrome 1 | 2025-03-03 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 39780207]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 27501770, 36497448, 26014290, external communications]. |
| Ambry Genetics | RCV002411441 | SCV002669649 | pathogenic | Hereditary cancer-predisposing syndrome | 2025-05-01 | criteria provided, single submitter | clinical testing | The c.783-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the TP53 gene. This pathogenic mutation has been detected in one individual with multiple early onset breast cancer diagnoses (Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305), and in a family meeting LFS diagnostic criteria (internal Ambry data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. 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. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
| Labcorp Genetics |
RCV000464087 | SCV000545354 | pathogenic | Li-Fraumeni syndrome | 2020-08-26 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 7 of the TP53 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 26014290, 27501770, Invitae). ClinVar contains an entry for this variant (Variation ID: 406603). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). For these reasons, this variant has been classified as Pathogenic. |