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Gene | FGFR2 |
Variant | M538I |
Impact List | missense |
Protein Effect | gain of function |
Gene Variant Descriptions | FGFR2 M538I (corresponds to M537I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). M538I confers a gain of function to the Fgfr2 protein as demonstrated by increased Fgfr2 kinase activity (PMID: 32723837, PMID: 23908597) and enhanced cell proliferation in the presence of ligand in cell culture (PMID: 23908597), and has been associated with decreased sensitivity to some FGFR inhibitors (PMID: 23908597). |
Associated Drug Resistance |
Transcript | NM_000141.4 |
gDNA | chr10:g.121498553C>G |
cDNA | c.1614G>C |
Protein | p.M538I |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_001320658 | chr10:g.121498547C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
NM_001144913 | chr10:g.121498556C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
NM_001320658.1 | chr10:g.121498547C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
NM_022970.3 | chr10:g.121498556C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
XM_006717710 | chr10:g.121500833C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
NM_001144913.1 | chr10:g.121498556C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
NM_000141.4 | chr10:g.121498553C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
XM_006717710.4 | chr10:g.121500833C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
NM_022970 | chr10:g.121498556C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
NM_000141 | chr10:g.121498553C>G | c.1614G>C | p.M538I | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
FGFR2 M538I | estrogen-receptor positive breast cancer | sensitive | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Mekinist (trametinib) treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). | 32723837 |
FGFR2 M538I | estrogen-receptor positive breast cancer | sensitive | FIIN-2 | Preclinical - Cell culture | Actionable | In a preclinical study, FIIN-2 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). | 32723837 |
FGFR2 M538I | estrogen-receptor positive breast cancer | sensitive | FIIN-3 | Preclinical - Cell culture | Actionable | In a preclinical study, FIIN-3 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). | 32723837 |
FGFR2 M538I | Advanced Solid Tumor | decreased response | Ponatinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with Iclusig (ponatinib) (PMID: 23908597). | 23908597 |
FGFR2 M538I | breast cancer | sensitive | FIIN-3 + Fulvestrant | Preclinical - Cell culture | Actionable | In a preclinical study, Faslodex (fulvestrant) and FIIN-3 combination treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). | 32723837 |
FGFR2 M538I | Advanced Solid Tumor | decreased response | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 M538I | Advanced Solid Tumor | decreased response | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 M538I | estrogen-receptor positive breast cancer | sensitive | AZD4547 | Preclinical - Cell culture | Actionable | In a preclinical study, AZD4547 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). | 32723837 |
FGFR2 M538I | estrogen-receptor positive breast cancer | sensitive | SHP099 | Preclinical - Cell culture | Actionable | In a preclinical study, SHP099 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). | 32723837 |
FGFR2 - INA FGFR2 M538I FGFR2 N550H FGFR2 N550T FGFR2 L618V FGFR2 H683L | intrahepatic cholangiocarcinoma | resistant | Debio 1347 | Case Reports/Case Series | Actionable | In a clinical case study, a patient with intrahepatic cholangiocarcinoma harboring an FGFR2-INA fusion developed progressive disease after initial response to Debio 1347 for 11.4 months and FGFR2 H683L, L618V, N550H, N550T, M538I mutations were identified post-progression (PMID: 31109923). | 31109923 |
FGFR2 - INA FGFR2 M538I FGFR2 N550H FGFR2 N550T FGFR2 L618V FGFR2 H683L | intrahepatic cholangiocarcinoma | sensitive | Futibatinib | Case Reports/Case Series | Actionable | In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-INA fusion with FGFR2 H683L, L618V, N550H, N550T, M538I mutations, responded to TAS-120 for 5.1 months before progressing due to acquired FGFR2 V565L and E566A mutations, detected in cell-free DNA (PMID: 31109923; NCT02052778). | 31109923 |
FGFR2 fusion FGFR2 M538I | intrahepatic cholangiocarcinoma | sensitive | Futibatinib | Preclinical - Cell culture | Actionable | In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). | 31109923 |
FGFR2 fusion FGFR2 M538I | intrahepatic cholangiocarcinoma | decreased response | Debio 1347 | Preclinical - Cell culture | Actionable | In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). | 31109923 |
FGFR2 fusion FGFR2 M538I | intrahepatic cholangiocarcinoma | decreased response | Infigratinib | Preclinical - Cell culture | Actionable | In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). | 31109923 |
Molecular Profile | Protein Effect | Treatment Approaches |
---|---|---|
FGFR2 M538I | gain of function | FGFR Inhibitor (Pan) FGFR2 Inhibitor |
FGFR2 - INA FGFR2 M538I FGFR2 N550H FGFR2 N550T FGFR2 L618V FGFR2 H683L | ||
FGFR2 fusion FGFR2 M538I |