Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001025418 | SCV001187601 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-06 | criteria provided, single submitter | clinical testing | The p.P219L variant (also known as c.656C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 656. The proline at codon 219 is replaced by leucine, 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 proficient at growth suppression and has no 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 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 limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV002552398 | SCV003006289 | uncertain significance | Li-Fraumeni syndrome | 2023-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 219 of the TP53 protein (p.Pro219Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 826488). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). 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. |
| Color Diagnostics, |
RCV001025418 | SCV004359994 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-24 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with leucine at codon 219 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that the mutant protein harboring this variant is functional in a human cell proliferation assay (PMID: 29979965). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |