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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

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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

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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