Gene Variant Detail

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Gene HRAS
Variant A59Rfs*32
Impact List frameshift
Protein Effect loss of function - predicted
Gene Variant Descriptions HRAS A59Rfs*32 indicates a shift in the reading frame starting at amino acid 59 and terminating 32 residues downstream causing a premature truncation of the 189 amino acid Hras protein (UniProt.org). Due to the loss of the GTP binding domain (UniProt.org), A59Rfs*32 is predicted to lead to a loss of Hras protein function resulting in inactivation of downstream signaling.
Associated Drug Resistance
Category Variants Paths

HRAS mutant HRAS inact mut HRAS A59Rfs*32

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Transcript NM_005343.4
gDNA chr11:g.533881_533882delCG
cDNA c.175_176delGC
Protein p.A59Rfs*32
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_001130442.2 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_176795.5 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_005343.4 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_001130442 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_005343 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_176795 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_005343.3 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_176795.4 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38
NM_001130442.3 chr11:g.533881_533882delCG c.175_176delGC p.A59Rfs*32 RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS inact mut thyroid cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited growth of thyroid cancer cells harboring an HRAS pathway activating mutation in cell culture (PMID: 21831957). 21831957
HRAS mutant Advanced Solid Tumor predicted - sensitive Everolimus Preclinical - Cell culture Actionable In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). 26544513
HRAS mutant transitional cell carcinoma resistant Trametinib Preclinical Actionable In a preclinical study, human urinary transitional cell carcinoma cells harboring mutant HRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). 26343583
HRAS mutant urinary bladder cancer sensitive Metformin Preclinical Actionable In a preclinical study, mouse models of bladder cancer harboring an HRAS mutation were sensitive to Glucophage (metformin), resulting in tumor growth reduction and prevention of hyperplasia regression (PMID: 26921394). 26921394
HRAS mutant Advanced Solid Tumor predicted - sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Selumetinib (AZD6244) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). 26544513
HRAS mutant transitional cell carcinoma predicted - sensitive Tipifarnib Phase II Actionable In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS missense (Q61R, G12S, G13R) or frameshift (V29Cfs*19) mutations, progression-free survival was significantly improved in patients harboring HRAS mutations (5.1 vs 0.8 months, HR=0.262) compared to wild-type patients (PMID: 32636318; NCT02535650). 32636318
HRAS mutant head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Phase II Actionable In a Phase II trial (AIM-HN), Zarnestra (tipifarnib) demonstrated safety and preliminary activity in patients with recurrent or metastatic head and neck squamous cell carcinoma harboring mutations in HRAS, resulting in an objective response rate of 20% (10/50, 1 complete and 9 partial responses), disease control rate of 48% (24/50), with stable disease in 14 patients, median progression-free survival of 2.6 mo, and median overall survival of 7 mo (Ann Oncol (2023) 34 (suppl_2): S1286-S1287; NCT03719690). detail...
HRAS mutant head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, head and neck squamous cell carcinoma cell lines harboring an HRAS mutation were sensitive to treatment with Zarnestra (tipifarnib), demonstrating reduced cell growth and decreased phosphorylation of Erk and Mek, and inhibition of spheroid viability in culture (PMID: 32727882). 32727882
HRAS mutant head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Phase II Actionable In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 55% (11/20) in patients with head and neck squamous cell carcinoma harboring HRAS missense mutations at a variant allele frequency over 20%, with nine patients achieved stable disease and a median progression-free survival of 5.6 months (PMID: 33750196; NCT02383927). 33750196
HRAS mutant medullary thyroid carcinoma sensitive Cabozantinib Guideline Actionable Cometriq (cabozantinib) is included in guidelines for patients with advanced or metastatic medullary thyroid carcinoma harboring RAS mutations (PMID: 31549998, PMID: 35491008; ESMO.org). 35491008 31549998 detail...
HRAS mutant medullary thyroid carcinoma sensitive Cabozantinib Phase III Actionable In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression-free survival (47 vs 8 weeks, HR 0.15, p=0.0317) compared to placebo in thyroid medullary carcinoma patients harboring RAS mutations (PMID: 27525386). 27525386
HRAS mutant breast cancer decreased response PI-273 Preclinical - Cell culture Actionable In a preclinical study, breast cancer cell lines harboring RAS mutations, including HRAS-mutant cell lines, demonstrated decreased sensitivity to growth inhibition by PI-273, in culture (PMID: 28827373). 28827373
HRAS mutant salivary gland cancer predicted - sensitive Tipifarnib Phase II Actionable In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 8% (1/12) in patients with recurrent or metastatic salivary gland cancer harboring HRAS mutations, with a median progression-free survival of 7 months (J Clin Oncol 38: 2020 (suppl; abstr 6504); NCT02383927). detail...
HRAS mutant ovarian cancer predicted - sensitive Alpelisib + Binimetinib Phase Ib/II Actionable In a Phase Ib study, Alpelisib (BYL719) in combination with Binimetinib (MEK162) demonstrated preliminary safety and efficacy in patients with RAS-mutant advanced solid tumors, including patients with ovarian cancer (J Clin Oncol 32:5s, 2014 (suppl; abstr 9051). detail...
HRAS mutant endometrial cancer sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of human endometrial cancer cells harboring mutant HRAS in culture (PMID: 26343583). 26343583
HRAS mutant Advanced Solid Tumor predicted - sensitive Binimetinib Preclinical - Cell culture Actionable In a preclinical study, Binimetinib (MEK162) inhibited growth and induced apoptosis in human solid tumor cell lines harboring HRAS mutations in culture (PMID: 26544513). 26544513