Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001223535 | SCV001395691 | uncertain significance | Li-Fraumeni syndrome | 2022-09-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 334 of the TP53 protein (p.Gly334Glu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 951578). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (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. |
| Baylor Genetics | RCV003469390 | SCV004206275 | uncertain significance | Adrenocortical carcinoma, hereditary | 2023-05-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004032479 | SCV005036092 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-25 | criteria provided, single submitter | clinical testing | The p.G334E variant (also known as c.1001G>A), located in coding exon 9 of the TP53 gene, results from a G to A substitution at nucleotide position 1001. The glycine at codon 334 is replaced by glutamic acid, an amino acid with similar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This variant is reported to have partially 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 (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration is located in the tetramerization domain of the TP53 protein, and renders the protein unable to form tetramers (Kawaguchi T et al. Oncogene, 2005 Oct;24:6976-81). 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. |