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 sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 164 of the TP53 protein (p.Lys164Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 32817165, 33138793, 38050059). ClinVar contains an entry for this variant (Variation ID: 246416). 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, 29979965, 30224644). 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 pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 38050059, 33138793].
"This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Pathogenic (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: TP53K164ETP53K164ESomaticNCBI 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 K164E mutation is likely oncogenic.Hide mutation effect description The TP53 K164E mutation is located in the DNA-binding domain of the protein. This mutation has been identified in ovarian cancer and is a statistically significant hotspot (PMID: 9699640). In vivo studies with yeast expressing TP53 K164E 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 K164E also demonstrated the mutation is inactivating as measured by reduced growth suppression activity as compared to wildtype (PMID: 29979965, 30224644). JAX-CKB: TP53 K164E lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). K164E confers a loss of function to the Tp53 protein as demonstrated by decreased transactivation of Tp53 target genes, decreased growth suppression, and loss of DNA binding in culture (PMID: 38050059).
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -151 bp |
| Donor Loss (DL) | 0.0 | -268 bp |
| Acceptor Gain (AG) | 0.0 | -168 bp |
| Donor Gain (DG) | 0.0 | -23 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)