Gene Variant Detail

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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

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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

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 act mut endometrial cancer sensitive Dovitinib Preclinical - Cell line xenograft Actionable In a preclinical study, both cell lines and cell line xenograft models of endometrial cancer with FGFR2 activating mutations showed greater sensitivity to Dovitinib (TKI258) as compared to FGFR2 wild-type (PMID: 23443805). 23443805
FGFR2 act mut Advanced Solid Tumor sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR2 in culture (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor predicted - sensitive Erdafitinib Phase I Actionable In a Phase I trial, Balversa (erdafitinib) treatment resulted in stable disease in 70% (16/23) and partial response in 22% (5/23) of patients with advanced solid tumors harboring FGFR 1-4 activating mutations (including amplifications, mutations and translocations), while no antitumor activity was observed in patients with unknown or no known changes in FGFR (PMID: 26324363; NCT01703481). 26324363
FGFR2 act mut Advanced Solid Tumor predicted - sensitive AZD4547 Phase II Actionable In a Phase II (MATCH) trial, AZD4547 treatment resulted in an overall response rate of 10.5% (2/19) in patients with advanced solid tumors harboring FGFR2 or 3 activating single nucleotide variants and a 6-month progression-free survival rate of 6%, with a partial response in 1 and stable disease in 2 of 12 patients with FGFR2 activating mutations (PMID: 32463741; NCT02465060). 32463741
FGFR2 act mut Advanced Solid Tumor sensitive Debio 1347 Phase I Actionable In a Phase I trial, Debio 1347 (CH5183284) dosing regimen has been determined in solid tumor patients with activating FGFR2 alterations (JCO, Vol 33, No 15_suppl (May 20 Supplement), 2015: 2540). detail...
FGFR2 act mut Advanced Solid Tumor decreased response Nintedanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR2 demonstrated reduced sensitivity to Ofev (Nintedanib) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor decreased response Cediranib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR2 demonstrated reduced sensitivity to inhibition of receptor phosphorylation and cell proliferation by Cediranib (AZD-2171) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR2 act mut Advanced Solid Tumor decreased response Brivanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR2 demonstrated reduced sensitivity to inhibition of receptor phosphorylation and cell proliferation by Brivanib (BMS-540215) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR2 act mut stomach carcinoma sensitive S-49076 Preclinical - Cell line xenograft Actionable In a preclinical study, S-49076 inhibited Met activation, resulting in growth inhibition of gastric carcinoma cells harboring FGFR2 activating mutations in culture and in cell line xenograft models (PMID: 23804704). 23804704
FGFR2 act mut Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited receptor phosphorylation and cell growth in transformed cells expressing constitutively active FGFR2 in culture (PMID: 22238366). 22238366
FGFR2 act mut bladder urothelial carcinoma sensitive Erdafitinib Guideline Actionable Balversa (erdafitinib) is included in guidelines for patients with advanced or metastatic bladder urothelial carcinoma harboring FGFR alterations (PMID: 34861372; ESMO.org). detail... 34861372
FGFR2 mutant cholangiocarcinoma sensitive Infigratinib Case Reports/Case Series Actionable In a Phase I trial, a patient with cholangiocarcinoma harboring an FGFR2 mutation demonstrated a decreased tumor burden when treated with Truseltiq (infigratinib) (PMID: 27870574). 27870574
FGFR2 mutant transitional cell carcinoma sensitive Erdafitinib Guideline Actionable Balversa (erdafitinib) is included in the guidelines for patients with advanced or metastatic urothelial carcinoma harboring Fgfr2 alterations after progression on platinum-based regimens (NCCN.org). detail...
FGFR2 mutant transitional cell carcinoma sensitive Erdafitinib FDA approved - Has Companion Diagnostic Actionable In a Phase II trial (BCL2001) that supported FDA approval, Balversa (erdafitinib) treatment resulted in an objective response rate of 40% (40/99, 3 complete response, 37 partial response) and a disease control rate of 80% in patients with metastatic or unresectable urothelial carcinoma harboring FGFR alterations (PMID: 31340094; NCT02365597). detail... 31340094 detail...
FGFR2 mutant endometrial cancer sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of endometrial cancer cells harboring FGFR2 mutations in culture (AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1249). detail...
FGFR2 mutant cholangiocarcinoma predicted - sensitive Erdafitinib Phase I Actionable In a Phase I trial, Balversa (erdafitinib) treatment resulted in an objective response rate of 27% (3/11) in patients with cholangiocarcinoma harboring FGFR genomic alterations, including 1 with FGFR2 mutation, 2 with FGFR3 mutations, and 8 with FGFR2 fusions (PMID: 31088831; NCT01703481). 31088831
FGFR2 mutant bladder urothelial carcinoma sensitive Erdafitinib Guideline Actionable Balversa (erdafitinib) is included in the guidelines for patients with advanced or metastatic urothelial carcinoma harboring Fgfr2 alterations after progression on platinum-based regimens (NCCN.org). detail...
FGFR2 mutant bladder urothelial carcinoma sensitive Erdafitinib FDA approved - Has Companion Diagnostic Actionable In a Phase II trial (BCL2001) that supported FDA approval, Balversa (erdafitinib) treatment resulted in an objective response rate of 40% (40/99, 3 complete response, 37 partial response) and a disease control rate of 80% in patients with metastatic or unresectable urothelial carcinoma harboring FGFR alterations (PMID: 31340094; NCT02365597). detail... 31340094 detail...
FGFR2 mutant endometrial cancer sensitive Infigratinib Preclinical Actionable In a preclinical study, Truseltiq (infigratinib) inhibited the growth of FGFR2-mutated endometrial cancer cells in vitro and in xenograft models (PMID: 23443805). 23443805
FGFR2 mutant Advanced Solid Tumor predicted - sensitive Debio 1347 Phase I Actionable In a Phase I trial, Debio 1347 treatment resulted in partial response in 10.5% (6/57) and stable disease in 28.1% (16/57) of patients with advanced solid tumors harboring genomic alterations of FGFR1/2/3, including amplifications, fusions, and mutations (PMID: 30745300; NCT01948297). 30745300
FGFR2 mutant Advanced Solid Tumor predicted - sensitive ICP-192 Phase I Actionable In a Phase I trial, ICP-192 (gunagratinib) was well-tolerated, and resulted in an overall response rate or 33.3% (4/12, 1 complete response, 3 partial response) and a disease control rate of 91.7% (11/12) in patients with advanced solid tumors harboring FGF/FGFR gene aberrations (J Clin Oncol 39, 2021 (suppl 15; abstr 4092); NCT03758664). detail...
FGFR2 mutant Advanced Solid Tumor sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, a variety of cancer cell lines harboring mutations in FGFR1, FGFR2, and/or FGFR3 demonstrated sensitivity to Pemazyre (pemigatinib) in culture and in cell line xenograft models, resulting in inhibition of tumor growth (Cancer Res 2015;75(15 Suppl):Abstract nr 771). detail...