Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001202958 | SCV001374094 | uncertain significance | Li-Fraumeni syndrome | 2019-06-17 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with glycine at codon 216 of the TP53 protein (p.Val216Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376671). 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 disrupts the Val216 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26014290, 24549055, 25669829, 12826609, 17724467, 21232794). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). |
| Ambry Genetics | RCV004678697 | SCV005177906 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-04-17 | criteria provided, single submitter | clinical testing | The p.V216G pathogenic mutation (also known as c.647T>G), located in coding exon 5 of the TP53 gene, results from a T to G substitution at nucleotide position 647. The valine at codon 216 is replaced by glycine, an amino acid with dissimilar properties. 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 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). Two other variants at the same codon, p.V216M (c.646G>A) and p.V216L (c.646G>T), have been detected in patients with features of Li-Fraumeni syndrome and demonstrated loss of function in mulitiple studies (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum Mol Genet, 2017 07;26:2812). 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 variant is interpreted as a disease-causing mutation. |