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Gene MAP2K1
Variant P124L
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions MAP2K1 P124L lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P124L confers a gain of function on the Map2k1 protein as demonstrated by increased Erk 1/2 phosphorylation (PMID: 19915144, PMID: 29483135) and Mek phosphorylation in cultured cells (PMID: 29483135) and also confers resistance to some Mek and Braf inhibitors in melanoma cells (PMID: 19915144).
Associated Drug Resistance Y
Category Variants Paths

MAP2K1 mutant MAP2K1 act mut MAP2K1 P124L

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Transcript NM_002755.4
gDNA chr15:g.66436825C>T
cDNA c.371C>T
Protein p.P124L
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_002755.3 chr15:g.66436825C>T c.371C>T p.P124L RefSeq GRCh38/hg38
XM_017022411 chr15:g.66436825C>T c.371C>T p.P124L RefSeq GRCh38/hg38
XM_017022411.3 chr15:g.66436825C>T c.371C>T p.P124L RefSeq GRCh38/hg38
NM_002755.4 chr15:g.66436825C>T c.371C>T p.P124L RefSeq GRCh38/hg38
NM_002755 chr15:g.66436825C>T c.371C>T p.P124L RefSeq GRCh38/hg38
XM_017022411.2 chr15:g.66436825C>T c.371C>T p.P124L RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600K MAP2K1 P124L melanoma decreased response Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600K and MAP2K1 P124L demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 25370473). 25370473
BRAF V600K MAP2K1 P124L melanoma sensitive VX-11e Preclinical Actionable In a preclinical study, VX-11e inhibited ERK signaling and reduced growth of a melanoma cell line harboring BRAF V600K and MAP2K1 P124L in culture (PMID: 25370473). 25370473
BRAF V600K MAP2K1 P124L melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited ERK signaling and reduced growth of a melanoma cell line harboring BRAF V600K and MAP2K1 P124L in culture (PMID: 25370473). 25370473
BRAF V600K MAP2K1 P124L melanoma predicted - resistant Dabrafenib + Trametinib Case Reports/Case Series Actionable In a clinical case study, Tafinlar (dabrafenib) and Mekinist (trametinib) combination treatment resulted in disease progression within one month in a metastatic melanoma patient harboring BRAF V600K and MAP2K1 P124L (PMID: 31980996). 31980996
BRAF V600E MAP2K1 P124L melanoma sensitive PLX4720 + Selumetinib Preclinical Actionable In a preclinical study, combined treatment with Koselugo (selumetinib) and PLX4720 inhibited growth of melanoma cells harboring BRAF V600E and expressing MAP2K1 P124L in culture (PMID: 19915144). 19915144
BRAF V600E MAP2K1 P124L melanoma resistant Selumetinib Preclinical Actionable In a preclinical study, expression of MAP2K1 P124L in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) in culture (PMID: 19915144). 19915144
BRAF V600E MAP2K1 P124L melanoma decreased response Trametinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124L demonstrated a decreased response to treatment with Mekinist (trametinib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 P124L melanoma predicted - resistant Vemurafenib Case Reports/Case Series Actionable In a clinical case study, Zelboraf (vemurafenib) treatment resulted in disease progression within 6 weeks in a metastatic melanoma patient harboring BRAF V600E and MAP2K1 P124L (PMID: 24265153). 24265153
BRAF V600E MAP2K1 P124L melanoma predicted - resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124L demonstrated a decreased response to treatment with Zelboraf (vemurafenib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 P124L melanoma resistant PLX4720 Preclinical - Cell culture Actionable In a preclinical study, expression of MAP2K1 P124L in melanoma cells harboring BRAF V600E conferred resistance to PLX4720 treatment in culture (PMID: 19915144). 19915144
BRAF V600E MAP2K1 P124L melanoma sensitive Cobimetinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Zelboraf (vemurafenib) and Cotellic (cobimetinib) synergistically inhibited viability of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 P124L in culture (PMID: 36442478). 36442478