Gene Variant Detail

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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

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Transcript NM_002755.3
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
XM_017022411 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
NM_002755 chr15:g.66436825C>T c.371C>T p.P124L RefSeq GRCh38/hg38
NM_002755.3 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
MAP2K1 P124L lymphatic system cancer predicted - sensitive Cobimetinib Case Reports/Case Series Actionable In a Phase II trial, treatment with Cotellic (cobimetinib) in patients with histiocytic neoplasms resulted in a PET overall response rate of 89% (16/18), with complete response in 72% (13/18) and partial response in 17% (3/18), and resulted in stable disease in 6% (1/18) of patients, including a complete response in a patient with mixed histiocytosis harboring MAP2K1 P124L (PMID: 30867592; NCT01953926). 30867592
MAP2K1 P124L melanoma resistant Selumetinib Preclinical Actionable In a preclinical study, transformed human melanoma cells expressing MAP2K1 P124L demonstrated resistance to the MEK inhibitor, Selumetinib (AZD6244) (PMID: 19915144). 19915144
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 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 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 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 V600E MAP2K1 P124L melanoma decreased response 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 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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 mutant Erdheim-Chester disease sensitive Cobimetinib Guideline Actionable Cotellic (cobimetinib) is included in guidelines as preferred first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring mutations in the MAPK pathway such as ARAF, NRAS, KRAS, MAP2K1, PIK3CA, or with no detectable mutations, or for whom testing is not available (NCCN Guidelines). detail...
MAP2K1 mutant Erdheim-Chester disease sensitive Trametinib Guideline Actionable Mekinist (trametinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring mutations in the MAPK pathway such as ARAF, NRAS, KRAS, MAP2K1, PIK3CA, or with no detectable mutations, or for whom testing is not available (NCCN Guidelines). detail...
Molecular Profile Protein Effect Treatment Approaches
MAP2K1 P124L gain of function
BRAF V600K MAP2K1 P124L
BRAF V600E MAP2K1 P124L