Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001059510 | SCV001224135 | uncertain significance | Li-Fraumeni syndrome | 2019-04-22 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with proline at codon 121 of the TP53 protein (p.Ser121Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant has not been reported in the literature in individuals with TP53-related conditions. An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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. This variant is not present in population databases (ExAC no frequency). |
| Gene |
RCV002286806 | SCV002577180 | uncertain significance | not provided | 2022-03-31 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate conflicting data: non-functional transactivation, but no loss of growth suppression activity (Kato et al., 2003; Kotler et al., 2018; Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 22768918, 15510160, 30224644, 29979965) |
| Ambry Genetics | RCV002451248 | SCV002615829 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-10 | criteria provided, single submitter | clinical testing | The p.S121P variant (also known as c.361T>C), located in coding exon 3 of the TP53 gene, results from a T to C substitution at nucleotide position 361. The serine at codon 121 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 loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). However, studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |