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Gene | FGFR2 |
Variant | N549H |
Impact List | missense |
Protein Effect | gain of function |
Gene Variant Descriptions | FGFR2 N549H lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N549H demonstrates resistance to FGFR inhibitors in the context of FGFR2-CLIP1 in culture (PMID: 31371345), and confers a gain of function to the Fgfr2 protein as indicated by disengagement of autoinhibitory mechanisms thereby resulting in constitutive activation and downstream pathway activation (PMID: 17525745, PMID: 17803937), elevated kinase activity in substrate phosphorylation assays (PMID: 28166054), a growth advantage relative to wild-type Fgfr2 in a competition assay, and increased transformation activity in cultured cells (PMID: 34272467). |
Associated Drug Resistance | Y |
Transcript | NM_000141.4 |
gDNA | chr10:g.121498522T>G |
cDNA | c.1645A>C |
Protein | p.N549H |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_001144919 | chr10:g.121488068T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
NM_000141.4 | chr10:g.121498522T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
NM_023029 | chr10:g.121488065T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
NM_023029.2 | chr10:g.121488065T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
NM_001144915.1 | chr10:g.121488065T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
NM_000141 | chr10:g.121498522T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
NM_001144915 | chr10:g.121488065T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
NM_001144919.1 | chr10:g.121488068T>G | c.1645A>C | p.N549H | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
FGFR2 N549H | Advanced Solid Tumor | sensitive | Futibatinib | Preclinical - Cell culture | Actionable | In a preclinical study, cells expressing FGFR2 N549H were sensitive to treatment with Futibatinib (TAS-120) in culture, demonstrating reduced cell viability (PMID: 34272467). | 34272467 |
FGFR2 N549H | Advanced Solid Tumor | sensitive | E7090 | Preclinical - Cell culture | Actionable | In a preclinical study, cells expressing FGFR2 N549H were sensitive to treatment with E7090 in culture, demonstrating reduced cell viability (PMID: 34272467). | 34272467 |
FGFR2 - ZMYM4 FGFR2 N549H FGFR2 N549K FGFR2 V564F FGFR2 E565A FGFR2 K659M | cholangiocarcinoma | predicted - resistant | Infigratinib | Case Reports/Case Series | Actionable | In a clinical case study, FGFR2 mutations E565A, K659M, N549H, N549K and V564F were identified in the cell-free DNA of a cholangiocarcinoma patient harboring FGFR2-ZMYM4 fusion after the patient progressed while on Truseltiq (infigratinib) treatment (PMID: 28034880). | 28034880 |
FGFR2 - OPTN FGFR2 N549H FGFR2 V564F FGFR2 E565A FGFR2 L617V FGFR2 K641R | cholangiocarcinoma | predicted - resistant | Infigratinib | Case Reports/Case Series | Actionable | In a clinical case study, FGFR2 mutations E565A, K641R, L617V, N549H and V564F were identified in the cell-free DNA of a cholangiocarcinoma patient harboring FGFR2-OPTN fusion after the patient progressed while on Truseltiq (infigratinib) treatment (PMID: 28034880). | 28034880 |
FGFR2 - CLIP1 FGFR2 N549H | Advanced Solid Tumor | resistant | Pemigatinib | Preclinical - Cell culture | Actionable | In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Pemazyre (pemigatinib) treatment in culture (PMID: 31371345). | 31371345 |
FGFR2 - CLIP1 FGFR2 N549H | Advanced Solid Tumor | resistant | Infigratinib | Preclinical - Cell culture | Actionable | In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Truseltiq (infigratinib) treatment in culture (PMID: 31371345). | 31371345 |
FGFR2 - CLIP1 FGFR2 N549H | Advanced Solid Tumor | resistant | AZD4547 | Preclinical - Cell culture | Actionable | In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to AZD4547 treatment in culture (PMID: 31371345). | 31371345 |
FGFR2 - CLIP1 FGFR2 N549H | cholangiocarcinoma | predicted - resistant | Pemigatinib | Case Reports/Case Series | Actionable | In a clinical case study, a cholangiocarinoma patient harboring FGFR2-CLIP1 demonstrated an initial partial response following treatment with Pemazyre (pemigatinib), but progressed after 5 months, and was determined to have an acquired FGFR2 N549H mutation (PMID: 31371345). | 31371345 |
FGFR2 - CLIP1 FGFR2 N549H | Advanced Solid Tumor | resistant | Erdafitinib | Preclinical - Cell culture | Actionable | In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Balversa (erdafitinib) treatment in culture (PMID: 31371345). | 31371345 |
FGFR2 - CLIP1 FGFR2 N549H | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) treatment inhibited viability of a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H in culture (PMID: 31371345). | 31371345 |
FGFR2 - CLIP1 FGFR2 N549H | Advanced Solid Tumor | resistant | Dovitinib | Preclinical - Cell culture | Actionable | In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Dovitinib (TKI258) treatment in culture (PMID: 31371345). | 31371345 |
FGFR2 - ATAD2 FGFR2 N549H | cholangiocarcinoma | predicted - resistant | Pemigatinib | Case Reports/Case Series | Actionable | In a Phase II trial (FIGHT-202), a cholangiocarcinoma patient harboring FGFR2-ATAD2 experienced disease progression after 8.8 months of treatment with Pemazyre (pemigatinib), and was found to have acquired FGFR2 N549H (PMID: 33218975; NCT02924376). | 33218975 |
FGFR2 - KIAA1217 FGFR2 N549D FGFR2 N549H FGFR2 N549K FGFR2 V564F FGFR2 V564I FGFR2 V564L FGFR2 E565A FGFR2 L617F FGFR2 L617V FGFR2 K659M FGFR2 Q746L | cholangiocarcinoma | predicted - resistant | Infigratinib | Case Reports/Case Series | Actionable | In a clinical case study, a patient with cholangiocarcinoma harboring an FGFR2-KIAA1217 fusion experienced disease progression after 10.6 months of treatment with Truseltiq (infigratinib) and was found to have acquired additional FGFR2 mutations, N549K, N549D, N549H, V564F, V564I, V564L, E565A, L617V, L617F, K659M, Q746L (PMID: 34250419). | 34250419 |
FGFR2 - WAC FGFR2 M537I FGFR2 M538L FGFR2 N549H FGFR2 N549K FGFR2 N549T FGFR2 L550F FGFR2 V564F FGFR2 V564I FGFR2 E565A FGFR2 D650Y FGFR2 N652S FGFR2 K659Q | cholangiocarcinoma | predicted - resistant | Infigratinib | Case Reports/Case Series | Actionable | In a clinical case study, a patient with cholangiocarcinoma harboring an FGFR2-WAC fusion experienced disease progression after 5.6 months of treatment with Truseltiq (infigratinib) and was found to have acquired additional FGFR2 mutations, M537I, M538L, N549H, N549T, N549K, L550F, V564F, V564I, E565A, D650Y, N652S, K659Q (PMID: 34250419). | 34250419 |