Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001021179 | SCV001182760 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-06-03 | criteria provided, single submitter | clinical testing | The p.S127T pathogenic mutation (also known as c.379T>A), located in coding exon 4 of the TP53 gene, results from a T to A substitution at nucleotide position 379. The serine at codon 127 is replaced by threonine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV001038263 | SCV001201727 | uncertain significance | Li-Fraumeni syndrome | 2021-08-23 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with threonine at codon 127 of the TP53 protein (p.Ser127Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 824232). Experimental studies have shown that this variant affects TP53 protein function (PMID: 12826609, 30224644, 29979965). 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. |
| Genome- |
RCV001021179 | SCV002582097 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV002290541 | SCV002582660 | uncertain significance | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing |