Gene Variant Detail

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Gene HRAS
Variant G12V
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions HRAS G12V does not lie within any known functional domains of the Hras protein (UniProt.org). G12V results in decreased Hras GTPase activity, loss of response to GTPase-activating proteins, leading to activation of downstream signaling pathways, and transformation of cultured cells (PMID: 24224811, PMID: 21850009, PMID: 6330729).
Associated Drug Resistance

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Transcript NM_005343.3
gDNA chr11:g.534288C>A
cDNA c.35G>T
Protein p.G12V
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_005343 chr11:g.534288C>A c.35G>T p.G12V RefSeq GRCh38/hg38
NM_176795.4 chr11:g.534288C>A c.35G>T p.G12V RefSeq GRCh38/hg38
NM_176795 chr11:g.534288C>A c.35G>T p.G12V RefSeq GRCh38/hg38
NM_001130442 chr11:g.534288C>A c.35G>T p.G12V RefSeq GRCh38/hg38
NM_001130442.2 chr11:g.534288C>A c.35G>T p.G12V RefSeq GRCh38/hg38
NM_005343.3 chr11:g.534288C>A c.35G>T p.G12V RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS G12V Advanced Solid Tumor sensitive Binimetinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS G12V demonstrated sensitivity to growth inhibition by Binimetinib (MEK162) in culture (PMID: 26544513). 26544513
HRAS G12V Advanced Solid Tumor sensitive Rigosertib Sodium Preclinical - Cell culture Actionable In a preclinical study, Rigosertib (ON 01910.Na) inhibited oncogenic transformation in fibroblast cells over-expressing HRAS G12V in culture (PMID: 27104980). 27104980
HRAS G12V urinary bladder cancer sensitive Everolimus + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Selumetinib (AZD6244) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 26544513). 26544513
HRAS G12V melanoma sensitive CI-1040 Preclinical Actionable In a preclinical study CI-1040 (PD-184352) inhibited melanoma progression in a transgenic zebrafish model of melanoma expressing HRAS G12V (PMID: 26267534). 26267534
HRAS G12V Advanced Solid Tumor sensitive Pz-1 Preclinical - Cell line xenograft Actionable In a preclinical study, Pz-1 reduced tumor growth in xenograft models of transformed cells over expressing HRAS G12V in a dose-dependent manner (PMID: 26126987). 26126987
HRAS G12V Advanced Solid Tumor sensitive WM-8014 Preclinical Actionable In a preclinical study, WM-8014 inhibited proliferation of a transformed mouse cell line expressing HRAS G12V in culture, and inhibited proliferation and induced senescence in a transgenic zebrafish model (PMID: 30069049). 30069049
HRAS G12V Advanced Solid Tumor predicted - sensitive SR9011 Preclinical - Cell culture Actionable In a preclinical study, SR9011 treatment resulted in apoptosis in HRAS G12V-induced senescent firbroblast cells in culture (PMID: 29320480). 29320480
HRAS G12V Advanced Solid Tumor resistant Panitumumab Preclinical Actionable In a preclinical study, tumor cells expressing HRAS G12V demonstrated resistance to treatment with Vectibix (panitumumab) (PMID: 22797062). 22797062
HRAS G12V Advanced Solid Tumor sensitive Binimetinib + Everolimus Preclinical - Cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) worked synergistically to inhibit growth of transformed cells expressing HRAS G12V in culture (PMID: 26544513). 26544513
HRAS G12V Advanced Solid Tumor sensitive Everolimus Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing HRAS G12V demonstrated sensitivity to growth inhibition by Afinitor (everolimus) in culture (PMID: 26544513). 26544513
HRAS G12V high grade glioma sensitive SF1126 Preclinical - Cell line xenograft Actionable In a preclinical study, SF1126 inhibited Akt activation, proliferation, and migration of transgenic mouse glioma cells expressing HRAS G12V in culture, and suppressed tumor growth in xenograft models (PMID: 25425962). 25425962
HRAS G12V urinary bladder cancer sensitive Binimetinib + Everolimus Preclinical - Cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a bladder cell line harboring HRAS G12V in culture (PMID: 26544513). 26544513
HRAS G12V Advanced Solid Tumor predicted - sensitive SR9009 Preclinical - Cell culture Actionable In a preclinical study, SR9009 treatment resulted in apoptosis in HRAS G12V-induced senescent firbroblast cells in culture (PMID: 29320480). 29320480
HRAS G12V Advanced Solid Tumor resistant Cetuximab Preclinical Actionable In a preclinical study, tumor cells expressing HRAS G12V demonstrated resistance to treatment with Erbitux (cetuximab) (PMID: 22797062). 22797062
FGFR3 dec exp FGFR3 wild-type HRAS G12V transitional cell carcinoma resistant AZD4547 Preclinical Actionable In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to AZD4547 in culture (PMID: 22869148). 22869148
FGFR3 dec exp FGFR3 wild-type HRAS G12V transitional cell carcinoma decreased response AZ8010 Preclinical Actionable In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to AZ8010 in culture (PMID: 22869148). 22869148
FGFR3 dec exp FGFR3 wild-type HRAS G12V transitional cell carcinoma resistant PD173074 Preclinical Actionable In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to PD173074 in culture (PMID: 22869148). 22869148
HRAS G12V HRAS R135A Advanced Solid Tumor resistant NS1 Preclinical Actionable In a preclinical study, introducing HRAS R135A mutation in transformed cells expressing HRAS G12V resulted in reduced binding of Hras to NS1, leading to resistance to Mapk pathway inhibition in cell culture (PMID: 27820802). 27820802
HRAS G12V HRAS R135K Advanced Solid Tumor resistant NS1 Preclinical Actionable In a preclinical study, introducing HRAS R135K mutation in transformed cells expressing HRAS G12V resulted in reduced binding of Hras to NS1, leading to resistance to Mapk pathway inhibition in cell culture (PMID: 27820802). 27820802
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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 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 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 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 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 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 56% (10/18) in patients with head and neck squamous cell carcinoma harboring HRAS missense mutations at a variant allele frequency over 20%, with a median progression-free survival of 6.1 months (J Clin Oncol 38: 2020 (suppl; abstr 6504); NCT02383927). 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 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) compared to placebo in thyroid medullary carcinoma patients harboring RAS mutations (PMID: 27525386). 27525386
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 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