Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000696673 | SCV000825246 | pathogenic | Li-Fraumeni syndrome | 2025-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 272 of the TP53 protein (p.Val272Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1737852; internal data). ClinVar contains an entry for this variant (Variation ID: 574679). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21343334, 27533082, 29979965, 30224644). This variant disrupts the p.Val272 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18511570, 23175693, 25584008, 29070607). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002422533 | SCV002680337 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-09-08 | criteria provided, single submitter | clinical testing | The p.V272L pathogenic mutation (also known as c.814G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 814. The valine at codon 272 is replaced by leucine, an amino acid with highly 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). Two other alterations at the same codon, p.V272M (c.814G>A) and p.V272G (c.815T>G), have been described in multiple families and/or patients meeting LFS criteria or with LFS related tumors (Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan; 98(1):E119-25; Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8; Renaux-Petel M et al. J. Med. Genet. 2017 Oct 25; Felix CA J. Clin. Invest. 1992 Feb;89(2):640-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved through mammals but not in all 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. |