Gene Variant Detail

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Gene HRAS
Variant Q61K
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions HRAS Q61K does not lie within any known functional domains of the Hras protein (UniProt.org). Q61K results in decreased Hras GTPase activity and leads to transformation of cells in culture (PMID: 3510078).
Associated Drug Resistance

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Transcript NM_005343.3
gDNA chr11:g.533875G>T
cDNA c.181C>A
Protein p.Q61K
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_176795.4 chr11:g.533875G>T c.181C>A p.Q61K RefSeq GRCh38/hg38
NM_005343.3 chr11:g.533875G>T c.181C>A p.Q61K RefSeq GRCh38/hg38
NM_001130442.2 chr11:g.533875G>T c.181C>A p.Q61K RefSeq GRCh38/hg38
NM_005343 chr11:g.533875G>T c.181C>A p.Q61K RefSeq GRCh38/hg38
NM_001130442 chr11:g.533875G>T c.181C>A p.Q61K RefSeq GRCh38/hg38
NM_176795 chr11:g.533875G>T c.181C>A p.Q61K RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS Q61K rhabdomyosarcoma sensitive LY3009120 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and LY3009120 combination treatment synergistically inhibited Erk phosphorylation, proliferation, and colony formation and induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture (PMID: 34737198). 34737198
HRAS Q61K rhabdomyosarcoma not predictive Rigosertib Preclinical - Cell culture Actionable In a preclinical study, Rigosertib (ON01910) inhibited cell viability and induced apoptosis and cell cycle arrest in rhabdomyosarcoma cells harboring HRAS Q61K in culture, however, cells with wild-type HRAS demonstrated the same response, and mechanistically, the response was found to be due to Rigosertib (ON0190) binding to tubulin (PMID: 33158997). 33158997
HRAS Q61K rhabdomyosarcoma no benefit Trametinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited ERK signaling and viability in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture, but did not inhibit ERK signaling in cell line xenograft models and led to tumor progression (PMID: 34737198). 34737198
HRAS Q61K rhabdomyosarcoma sensitive LY3009120 + LY3214996 Preclinical - Cell line xenograft Actionable In a preclinical study, LY3214996 and LY3009120 combination treatment synergistically induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture and induced tumor growth regression in a xenograft model (PMID: 34737198). 34737198
HRAS Q61K rhabdomyosarcoma sensitive LY3214996 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and LY3214996 combination treatment synergistically inhibited growth and induced apoptosis and cell cycle arrest in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture and induced tumor regression in a xenograft model (PMID: 34737198). 34737198
BRAF G466E HRAS Q61K melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) reduced ERK signaling and inhibited proliferation of a melanoma cell line harboring BRAF G466E and HRAS Q61K in culture (PMID: 28783719). 28783719
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS act mut salivary gland carcinoma sensitive Tipifarnib Clinical Study Actionable In a clinical study, Zarnestra (tipifarnib) treatment resulted in an overall response rate of 8% (n=13) with one ongoing partial response with a duration of 14 months and stable disease as the best response in 58% (7/12) of evaluable patients with HRAS-mutant metastatic salivary gland carcinoma, and a median overall survival of 18 months, and a median progression-free survival of 7 months (PMID: 32557577). 32557577
HRAS act mut Advanced Solid Tumor no benefit Selumetinib Clinical Study - Cohort Actionable In a Phase II trial (MATCH), Koselugo (selumetinib) treatment resulted in a 15% (3/20) six-month progression-free survival rate, no objective responses, and did not lead to tumor regression in pediatric patients with advanced solid tumors including high grade glioma (n=8) and rhabdomyosarcoma (n=7) that harbored MAPK pathway alterations including activating HRAS, KRAS, or NRAS mutations, BRAF V600E, or inactivating NF1 mutations (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 10008; NCT03213691, NCT03155620). detail...
HRAS act mut transitional cell carcinoma predicted - sensitive Tipifarnib Phase II Actionable In a Phase II trial, Zarnestra (tipifarnib) demonstrated safety and preliminary efficacy in patients with metastatic urothelial carcinoma harboring HRAS mutations (n=14) or STK11:rs2075606, 3 of 4 patients achieved progression-free survival at 6 months harbored HRAS activating mutations, and no response was observed in HRAS wild-type patients (J Clin Oncol 38: 2020 (suppl; abstr 5086); NCT02535650). detail...
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 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 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
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 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 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 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 thyroid gland medullary 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 thyroid gland medullary 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 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 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 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 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...