Description
The p.E258K pathogenic mutation (also known as c.772G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. The p.E258K variant was first reported in a patient diagnosed with breast cancer at 34 whose tumor demonstrated loss of heterozygosity (LOH), and whose family met classic LFS criteria with a history of early onset sarcomas, and brain tumors (Malkin D et al. Science. 1990 Nov;250:1233-8). This variant has also been reported in a family with a strong history of gastric cancers, and in an individual with glioblastoma multiforme (Masciari S et al. Genet. Med. 2011 Jul;13:651-7; Huang KL et al. Cell, 2018 04;173:355-370.e14). Yeast based functional studies showed this alteration to have loss of transactivation capacity, and dominant negative effect (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies on this variant conducted in mammalian cells showed inability to suppress growth, and a protein binding profile indicative of a mutant protein conformation (Frebourg T et al. Proc. Natl. Acad. Sci. U.S.A., 1992 Jul;89:6413-7). Additional studies conducted in human cell lines also 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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 alteration is interpreted as a disease-causing mutation.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
