Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| NM_000546.6 | MANE Select | 2512 nt | 143–1324 |
| NM_000546.4 | Alternative | 2586 nt | 198–1379 |
| NM_000546.2 | Alternative | 2629 nt | 252–1433 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe p.R248L pathogenic mutation (also known as c.743G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 743. The arginine at codon 248 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in a cohort of Chinese individuals at an high risk for breast cancer (Li JY et al. Int J Cancer, 2019 Jan;144:281-289). 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 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 U S A, 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98; Jordan JJ et al. Mol Cancer Res, 2010 May;8:701-16). 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 alteration is located at a position or in a region that is critical for protein function (Ambry internal data). 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.
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 248 of the TP53 protein (p.Arg248Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 29752822). ClinVar contains an entry for this variant (Variation ID: 230253). 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: 9290701, 12826609, 20407015, 25584008). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 8062826, 25584008]. This variant is expected to disrupt protein structure [Myriad internal data].
"This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories) and as Likely pathogenic (4 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: TP53R248LTP53R248LSomaticNCBI Gene:7157|Show additional gene information Variant OverviewTP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.The TP53 R248L mutation is likely oncogenic.Hide mutation effect description The TP53 R248L mutation is located in the protein's DNA binding domain. Expression of this mutant in TP53-null cells resulted in decreased transactivation of p53 target genes, as a measured by a luciferase reporter assay (PMID: 25584008). Additionally, the TP53 R248L mutation failed to suppress colony growth in a colony reduction assay compared to wildtype TP53 (PMID: 25584008). Ovarian cancer patient samples and mouse models expressing this mutation were sensitive to an amyloid aggregate TP53 inhibitor as evidenced by apoptosis assays. Some TP53 mutations have been shown to form amyloid aggregates that leads to inactivation of the TP53 protein. Responsiveness of this variant to amyloid aggregate inhibitors suggest that this is a loss-of-function mutation (PMID: 26748848). JAX-CKB: TP53 R248L is a hotspot mutation that lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). R248L results in decreased Tp53 transactivation and repression, and resistance to apoptosis in cell culture (PMID: 8336941, PMID: 20570896, PMID: 18566217).
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 23 bp |
| Donor Loss (DL) | 0.0 | -39 bp |
| Acceptor Gain (AG) | 0.0 | -407 bp |
| Donor Gain (DG) | 0.0 | 31 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PS3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
BP4 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)