Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000548437 | SCV000629862 | pathogenic | Li-Fraumeni syndrome | 2024-12-02 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 244 of the TP53 protein (p.Gly244Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 458560). 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, 16461914, 29979965, 30224644). This variant disrupts the p.Gly244 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16494995, 18511570, 25925845, 26818906, 29470806). 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 | RCV002384069 | SCV002674390 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-06-14 | criteria provided, single submitter | clinical testing | The p.G244A pathogenic mutation (also known as c.731G>C), located in coding exon 6 of the TP53 gene, results from a G to C substitution at nucleotide position 731. The glycine at codon 244 is replaced by alanine, 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 alteration at the same codon, p.G244S (c.730G>A), has been detected in Li Fraumeni syndrome families, and was shown to segregate with disease in one Chinese family diagnosed with LFS (Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Hu H et al. Sci Rep. 2016 Jan;6:20221). This amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV004023789 | SCV004933370 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-16 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Institute of Medical Sciences, |
RCV001255675 | SCV001432240 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research |