Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001202791 | SCV001373918 | pathogenic | Li-Fraumeni syndrome | 2021-01-12 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 16000567, 16322298, 29979965). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects TP53 protein function (PMID: 12826609, 30224644, 29979965). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 29470806, Invitae). ClinVar contains an entry for this variant (Variation ID: 934410). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 127 of the TP53 protein (p.Ser127Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. |
| Ambry Genetics | RCV002365911 | SCV002624718 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-26 | criteria provided, single submitter | clinical testing | The p.S127P pathogenic mutation (also known as c.379T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 379. The serine at codon 127 is replaced by proline, 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). Another pathogenic alteration at the same codon, p.S127T (c.379T>A), has been shown to also have non-functional transactivation in yeast based assays, be deficient at growth suppression, and have a dominant negative effect (Ambry internal data; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; 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. |