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Gene | NRAS |
Variant | Q61X |
Impact List | missense |
Protein Effect | unknown |
Gene Variant Descriptions | NRAS Q61X indicates any NRAS missense mutation that results in replacement of the glutamine (Q) at amino acid 61 by a different amino acid. NRAS Q61 mutations are hotspot mutations that often result in a loss of Nras GTPase activity and activation of downstream pathways (PMID: 27664710, PMID: 28666118, PMID: 22589270, PMID: 26985062). |
Associated Drug Resistance | |
Category Variants Paths |
NRAS mutant NRAS exon3 NRAS Q61X |
Transcript | NM_002524.5 |
gDNA | chr1:g.114713907_114713909 |
cDNA | c.181_183 |
Protein | p.Q61 |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_002524.5 | chr1:g.114713907_114713909 | c.181_183 | p.Q61 | RefSeq | GRCh38/hg38 |
NM_002524.4 | chr1:g.114713907_114713909 | c.181_183 | p.Q61 | RefSeq | GRCh38/hg38 |
NM_002524 | chr1:g.114713907_114713909 | c.181_183 | p.Q61 | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
NRAS Q61X | melanoma | sensitive | Binimetinib + Ribociclib | Phase Ib/II | Actionable | In a Phase Ib/II trial, Kisqali (ribociclib) plus Mektovi (binimetinib) was well tolerated in NRAS-mutant melanoma patients and resulted in an overall response rate (ORR) of 19.5% (8/41; all PR), disease control rate of 70.7% (29/41), median duration of response of 10.3 months, median progression-free survival of 3.7 months, and median overall survival (OS) of 11.3 months in the phase II cohort, and a response rate of 22.9% (16/70) in patients with an NRAS Q61 mutation overall (PMID: 35294522; NCT01781572). | 35294522 |
NRAS Q61X | colorectal cancer | resistant | Cetuximab | FDA contraindicated | Actionable | Erbitux (cetuximab) treatment of colorectal cancer patients with NRAS exon 3, codon 61 mutations is contraindicated (FDA.gov). | detail... |
NRAS Q61X | colorectal cancer | unknown | Binimetinib | Phase II | Actionable | In a Phase II trial (MATCH), Mektovi (binimetinib) treatment did not demonstrate promising efficacy in patients with advanced solid tumors harboring NRAS mutations at codon 12 (n=17), 13 (n=8), or 61 (n=22), however, colorectal cancer patients harboring NRAS Q61 mutations (n=8) achieved longer overall survival (HR 0.34, p=0.03) and progression-free survival (HR 0.23, p=0.007) compared to those harboring mutations at G12 or G13 (n=16) (PMID: 33637626; NCT02465060). | 33637626 |
NRAS Q61X | Advanced Solid Tumor | unknown | Binimetinib | Phase II | Actionable | In a Phase II trial (MATCH), Mektovi (binimetinib) therapy led to a nonpromising objective response rate of 2.1% (1/47) in patients (pts) with advanced solid tumors harboring NRAS G12/13 or Q61 mutations, Q61-mutant pts achieved longer overall survival (13.1 vs 5.5 mo, p=0.04) and progression-free survival (5.8 vs 1.8 mo, p=0.006) compared to G12/13-mutant pts examining all tumor types, but not when colorectal caner was excluded (HR 0.84, p=0.70; HR 0.67, p=0.4, respectively) (PMID: 33637626; NCT02465060). | 33637626 |
NRAS Q61X | colorectal cancer | resistant | Panitumumab | FDA contraindicated | Actionable | Vectibix (panitumumab) treatment of colorectal cancer patients with NRAS exon 3, codon 61 mutations is contraindicated (FDA.gov). | detail... |
NRAS Q61X | myelodysplastic syndrome | not applicable | N/A | Guideline | Prognostic | NRAS Q61X is associated with a poor prognosis in patients with myelodysplastic syndrome (NCCN.org). | detail... |
NRAS Q61X | melanoma | predicted - sensitive | Tunlametinib | Phase II | Actionable | In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate (ORR) of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations, with an ORR of 41.3% in patients with an NRAS Q61 mutation (n=75) (PMID: 38479118; NCT05217303). | 38479118 |