Gene Variant Detail

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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

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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

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS G12D acute myeloid leukemia sensitive Binimetinib Preclinical Actionable In a preclinical study, Binimetinib (MEK162) inhibited growth of acute myeloid leukemia cells that have been demonstrated to harbor NRAS G12D in culture and decreased disease burden in xenograft models with NRAS G12D (PMID: 24569456, PMID: 11238126). 24569456 11238126
NRAS G12D acute myeloid leukemia sensitive Alpelisib + Binimetinib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Alpelisib (BYL719) inhibited proliferation in a human acute myeloid leukemia (AML) cell line harboring NRAS G12D in culture, and decreased disease burden in xenograft models (PMID: 24569456). 24569456
NRAS G12D Advanced Solid Tumor sensitive N-Arachidonoyl Dopamine Preclinical - Cell culture Actionable In a preclinical study, N-Arachidonoyl Dopamine (NADA) disrupted NRAS protein membrane localization and decreased NRAS downstream signaling, and inhibited proliferation and induced cell death in transformed cells expressing NRAS G12D in culture (PMID: 27760835). 27760835
NRAS G12D Advanced Solid Tumor no benefit NS1 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NRAS G12D did not respond to treatment with NS1 in culture, resulting in sustained downstream signaling and cell transformation (PMID: 27820802). 27820802
NRAS G12D B-lymphoblastic leukemia/lymphoma predicted - sensitive Anti-CD19 CAR-T cells Case Reports/Case Series Actionable In a clinical case study, treatment with an investigational anti-CD19 CAR-T cells therapy resulted in rapid elimination of leukemic cells, including a subclone harboring NRAS G12D, in a patient with relapsed Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia, the NRAS G12D subclone remained undetectable at disease progression 6 weeks after treatment (PMID: 31905241). 31905241
NRAS G12D ovarian cancer predicted - resistant BI-3406 Preclinical - Cell culture Actionable In a preclinical study, BI-3406 treatment failed to inhibit growth of ovarian cancer cells harboring NRAS G12D in culture (PMID: 32816843). 32816843
NRAS G12D colorectal cancer predicted - sensitive GI-4000 Phase I Actionable In a Phase I trial, GI-4000 was well tolerated, induced immune response in 61.3% (19/31) of evaluable subjects, and resulted in stable disease as best response in 18% (6/33) of patients with advanced pancreatic or colorectal cancer harboring KRAS mutations, including KRAS G12C (n=3), KRAS G12D (n=6), KRAS G12V (n=8), KRAS Q61L (n=1), and NRAS G12D (n=1) in patients with colorectal cancer (PMID: 29528991). 29528991
NRAS G12D melanoma sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, ASTX029 treatment inhibited growth of a melanoma cell line harboring NRAS G12D in culture (PMID: 34330842). 34330842
NRAS G12D acute myeloid leukemia sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring NRAS G12D were sensitive to treatment with ASTX029 in culture (PMID: 34330842). 34330842
NRAS G12D melanoma predicted - sensitive Tunlametinib Case Reports/Case Series Actionable In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate 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 including NRAS Q61R (40%), Q61K (29.5%), and G12D (9.5%) (PMID: 38479118; NCT05217303). 38479118
NRAS G12D Advanced Solid Tumor sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation of a cell line expressing NRAS G12D in culture (PMID: 37164118). 37164118
NRAS G12D multiple myeloma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, a multiple myeloma cell line harboring NRAS G12D was sensitive to treatment with Mekinist (trametinib) in culture, demonstrating decreased cell viability (PMID: 37339170). 37339170
NRAS G12D multiple myeloma no benefit MRTX-1133 Preclinical - Cell culture Actionable In a preclinical study, a multiple myeloma cell line harboring NRAS G12D was not sensitive to treatment with MRTX1133 in culture (PMID: 37339170). 37339170
NRAS G12D Advanced Solid Tumor no benefit MRTX-1133 Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing NRAS G12D were not sensitive to treatment with MRTX1133 (PMID: 37339170). 37339170
NRAS G12D acute myeloid leukemia resistant RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line harboring NRAS G12D was resistant to RMC-4550 treatment in culture (PMID: 37992684). 37992684
NRAS G12D acral lentiginous melanoma predicted - sensitive Tovorafenib Case Reports/Case Series Actionable In a clinical case study, Ojemda (tovorafenib) treatment resulted in a partial response with therapy lasting at least 7.5 years in a patient with metastatic acral melanoma harboring NRAS G12D (PMID: 39001563). 39001563