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
OpenThis 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].
The p.R280S pathogenic mutation (also known as c.840A>T), located in coding exon 7 of the TP53 gene, results from an A to T substitution at nucleotide position 840. The arginine at codon 280 is replaced by serine, an amino acid with dissimilar 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). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 serine, which is neutral and polar, at codon 280 of the TP53 protein (p.Arg280Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypodiploid acute lymphoblastic leukemia (PMID: 23334668, 26580448, 29489754). ClinVar contains an entry for this variant (Variation ID: 988616). 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%. 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.
"This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratories) and as Uncertain significance (1 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: TP53R280STP53R280SSomaticNCBI 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 R280S mutation is likely oncogenic.Hide mutation effect description The TP53 R280S mutation is located in the DNA-binding domain of the protein. This mutation has been identified in squamous cell carcinoma and is a statistically significant hotspot (PMID: 10761706). In vivo studies with yeast expressing TP53 R280S demonstrated that the mutation is inactivating as measured by the loss of transactivational activity as compared to wildtype (PMID: 27328919, 12826609). In vitro studies with various human cancer cell lines expressing TP53 R280S also demonstrated the mutation is inactivating as measured by reduced growth suppression activity as compared to wildtype (PMID: 29979965, 30224644). JAX-CKB: No results found
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -441 bp |
| Donor Loss (DL) | 0.0 | 111 bp |
| Acceptor Gain (AG) | 0.01 | 33 bp |
| Donor Gain (DG) | 0.0 | -79 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)