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Gene | NRAS |
Variant | G12D |
Impact List | missense |
Protein Effect | loss of function |
Gene Variant Descriptions | NRAS G12D is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). G12D confers a loss of function on Nras protein as indicated by decreased intrinsic GTPase activity, reduced sensitivity to GTPase-activating proteins, leading to accumulation of GTP-bound Nras, activation of downstream signaling, and transformation of cultured cells (PMID: 19075190, PMID: 25252692). |
Associated Drug Resistance | |
Category Variants Paths |
NRAS mutant NRAS act mut NRAS G12D NRAS mutant NRAS exon2 NRAS G12X NRAS G12D |
Transcript | NM_002524.5 |
gDNA | chr1:g.114716126C>T |
cDNA | c.35G>A |
Protein | p.G12D |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_002524 | chr1:g.114716126C>T | c.35G>A | p.G12D | RefSeq | GRCh38/hg38 |
NM_002524.4 | chr1:g.114716126C>T | c.35G>A | p.G12D | RefSeq | GRCh38/hg38 |
NM_002524.5 | chr1:g.114716126C>T | c.35G>A | p.G12D | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
BRAF D594G NRAS G12D | melanoma | sensitive | AZ628 | Preclinical - Cell culture | Actionable | In a preclinical study, AZ628 inhibited proliferation of melanoma cell lines harboring both BRAF D594G and NRAS G12D in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | sensitive | TAK-632 | Preclinical - Cell culture | Actionable | In a preclinical study, TAK-632 inhibited proliferation of melanoma cell lines harboring both BRAF D594G and NRAS G12D in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | decreased response | PLX7904 | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to PLX7904 in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | decreased response | Vemurafenib | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to Zelboraf (vemurafenib) in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | decreased response | Dabrafenib | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | sensitive | Binimetinib + Encorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Mektovi (binimetinib) and Braftovi (encorafenib) resulted in a synergistic effect in melanoma cells harboring BRAF D594G and NRAS G12D, with decreased cell viability and Erk phosphorylation and increased apoptosis in culture (PMID: 35385748). | 35385748 |
DNMT3A R882H NRAS G12D | acute myeloid leukemia | sensitive | I-BET151 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, an acute myeloid leukemia cell line harboring DNMT3A R882H and NRAS G12D mutations demonstrated reduced proliferation and downregulation of a DNMT3A R882H associated gene expression profile upon I-BET151 treatment in culture, and I-BET151 treatment delayed the onset of leukemia symptoms and improved survival in xenograft mouse models derived from these cells (PMID: 31164355). | 31164355 |
DNMT3A R882H NRAS G12D | acute myeloid leukemia | sensitive | Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, an acute myeloid leukemia cell line xenograft model harboring DNMT3A R882H and NRAS G12D was sensitive to Mekinist (trametinib), demonstrating impaired disease progression and improved survival (PMID: 31164355). | 31164355 |
DNMT3A R882H NRAS G12D | acute myeloid leukemia | sensitive | I-BET151 + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, an acute myeloid leukemia cell line xenograft model harboring DNMT3A R882H and NRAS G12D treated with combined I-BET151 and Mekinist (trametinib) demonstrated impaired disease progression and improved survival superior to either therapy alone (PMID: 31164355). | 31164355 |
FLT3 exon 14 ins NRAS G12D | acute myeloid leukemia | predicted - sensitive | Dubermatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Dubermatinib (TP-0903) inhibited growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation and NRAS G12D in culture (PMID: 33268594). | 33268594 |
FLT3 exon 14 ins NRAS G12D | acute myeloid leukemia | predicted - resistant | Gilteritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Xospata (gilteritinib) failed to inhibit growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation and NRAS G12D in culture (PMID: 33268594). | 33268594 |
FLT3 exon 14 ins FLT3 D835X NRAS G12D NRAS G12S | acute myeloid leukemia | predicted - resistant | Gilteritinib | Case Reports/Case Series | Actionable | In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS G12S and G12D (PMID: 31088841). | 31088841 |
CBL Q367_E373delinsRLK FLT3 exon 14 ins FLT3 D835X NRAS G12D | acute myeloid leukemia | predicted - resistant | Gilteritinib | Case Reports/Case Series | Actionable | In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS G12D and CBL Q367_E373delinsRLK (PMID: 31088841). | 31088841 |
NRAS G12D NRAS L95H | Advanced Solid Tumor | sensitive | MRTX-1133 | Preclinical - Cell culture | Actionable | In a preclinical study, cultured cells expressing NRAS G12D and NRAS L95H were sensitive to treatment with MRTX1133, demonstrating decreased cell viability (PMID: 37339170). | 37339170 |