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Gene | TP53 |
Variant | R248W |
Impact List | missense |
Protein Effect | loss of function |
Gene Variant Descriptions | TP53 R248W is a hotspot mutation that lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). R248W results in interaction with Tbk1 leading to decreased Tbk1 and Irf3 phosphorylation and loss of Irf3 activation in culture (PMID: 33545063), disrupts Dnmt3a complex formation similar to wild-type Tp53 (PMID: 31640986), however, results in increased proliferation, migration, invasion, and protein stability and altered subcellular localization in culture (PMID: 37030635), increased tumorigenesis in mice, and leads to decreased ATM activation, resulting in increased genetic instability (PMID: 17417627, PMID: 14743206). |
Associated Drug Resistance | |
Category Variants Paths |
TP53 mutant TP53 exon7 TP53 R248W TP53 mutant TP53 inact mut TP53 R248W |
Transcript | NM_000546.6 |
gDNA | chr17:g.7674221G>A |
cDNA | c.742C>T |
Protein | p.R248W |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_001126114 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126113 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126113.2 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_000546.5 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001407268.1 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001407264.1 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001407270.1 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126113.3 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_000546 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126114.2 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126112.3 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001407266.1 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001407262.1 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126114.3 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126112.2 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_001126112 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
NM_000546.6 | chr17:g.7674221G>A | c.742C>T | p.R248W | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
TP53 R248W VHL inact mut | clear cell renal cell carcinoma | resistant | PT2399 | Preclinical - Cell culture | Actionable | In a preclinical study, TP53 R248W was associated with resistance to PT2399 in VHL-defective clear cell renal cell carcinoma cell lines in culture (PMID: 27595393). | 27595393 |
RB1 K240Sfs*22 TP53 R248W | Her2-receptor negative breast cancer | predicted - resistant | Fulvestrant + Palbociclib | Case Reports/Case Series | Actionable | In a clinical case study, RB1 K240Sfs*22 and TP53 R248W were identified in the circulating tumor DNA of a patient with estrogen receptor positive, progesterone receptor positive, and Erbb2 (Her2)-negative, invasive ductal carcinoma at the time of disease progression after 5 months of Ibrance (palbociclib) and Faslodex (fulvestrant) combination treatment (PMID: 29236940). | 29236940 |
JAK2 V617F TP53 R248W | acute myeloid leukemia | predicted - sensitive | IMG-7289 | Preclinical - Cell culture | Actionable | In a preclinical study, IMG-7289 treatment led to inhibition of colony formation, increased apoptosis and induction of cell cycle arrest in an acute myeloid leukemia cell line harboring JAK2 V617F and TP53 R248W in culture (PMID: 31723778). | 31723778 |
JAK2 V617F TP53 R248W | acute myeloid leukemia | predicted - sensitive | IMG-7289 + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, combination treatment with Jakafi (ruxolitinib) and IMG-7289 led to synergistic inhibition of colony formation and apoptosis induction in an acute myeloid leukemia cell line harboring JAK2 V617F and TP53 R248W in culture (PMID: 31723778). | 31723778 |