HRAS Q61G: Gene Variant Detail - Cancer Knowledgebase (CKB)

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Gene	HRAS
Variant	Q61G
Impact List	missense
Protein Effect	loss of function - predicted
Gene Variant Descriptions	HRAS Q61G does not lie within any known functional domains of the Hras protein (UniProt.org). Q61G results in decreased Hras GTPase activity in an in vitro assay and is weakly transforming in culture (PMID: 3510078), and therefore, is predicted to lead to a loss of Hras protein function and activation of downstream signaling.
Associated Drug Resistance
Category Variants Paths	HRAS mutant HRAS act mut HRAS Q61G HRAS mutant HRAS Q61X HRAS Q61G

Variant Reference Transcript
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Transcript	NM_005343.4
gDNA	chr11:g.533874_533875delCAinsGG
cDNA	c.181_182delCAinsGG
Protein	p.Q61G
Source Database	RefSeq
Genome Build	GRCh38/hg38

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Showing 1 to 9 of 9 entries

Transcript	gDNA	cDNA	Protein	Source Database	Genome Build
NM_001130442	chr11:g.533874_533875delTGinsCC	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_001130442.2	chr11:g.533874_533875delCAinsGG	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_001130442.3	chr11:g.533874_533875delCAinsGG	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_005343	chr11:g.533874_533875delTGinsCC	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_005343.3	chr11:g.533874_533875delCAinsGG	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_005343.4	chr11:g.533874_533875delCAinsGG	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_176795	chr11:g.533874_533875delTGinsCC	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_176795.4	chr11:g.533874_533875delCAinsGG	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38
NM_176795.5	chr11:g.533874_533875delCAinsGG	c.181_182delCAinsGG	p.Q61G	RefSeq	GRCh38/hg38

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
HRAS act mut	Advanced Solid Tumor	resistant	Dabrafenib	FDA contraindicated	Actionable	Tafinlar (dabrafenib) is not indicated for patients who have developed non-cutaneous, RAS-mutant malignancies (FDA.gov).	detail... detail...
HRAS act mut	Advanced Solid Tumor	resistant	Encorafenib	FDA contraindicated	Actionable	Braftovi (encorafenib) is not indicated for patients who have developed non-cutaneous, RAS-mutant malignancies (FDA.gov).	detail... detail...
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 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	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	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	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	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 Mektovi (binimetinib) 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 act mut	Advanced Solid Tumor	no benefit	Selumetinib	Clinical Study - Cohort	Actionable	In a Phase II trial (Pediatric MATCH), Koselugo (selumetinib) treatment was tolerated but did not result in an objective response in pediatric patients with advanced solid tumors including high-grade glioma (n=8) and rhabdomyosarcoma (n=7) harboring MAPK pathway alterations including BRAF V600E (n=2), activating KRAS (n=8)/HRAS (n=1)/NRAS (n=3) or inactivating NF1 (n=7) mutations, with a 6-month progression-free survival of 15% (3/20) and 3 stable disease as best response (PMID: 35363510; NCT03213691).	35363510
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	predicted - sensitive	BAY 11-7082	Preclinical - Cell line xenograft	Actionable	In a preclinical study, BAY 11-7082 induced apoptosis and decreased Akt signaling, viability, and colony formation in cancer cells harboring activating HRAS mutations in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38982514).	38982514
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	Advanced Solid Tumor	predicted - sensitive	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mektovi (binimetinib) inhibited growth and induced apoptosis in human solid tumor cell lines harboring HRAS mutations in culture (PMID: 26544513).	26544513
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	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	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	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	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

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HRAS Q61GGene Variant Detail

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HRAS Q61G
Gene Variant Detail