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Gene FGFR1
Variant N546K
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions FGFR1 N546K lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). N546K does not confer a growth advantage in a competition assay (PMID: 34272467), but results in increased Fgfr1 protein nuclear localization, Erk, Akt, and Stat3 phosphorylation (PMID: 35488346), and kinase activity, and is transforming in cultured cells (PMID: 26179511, PMID: 23817572, PMID: 29533785).
Associated Drug Resistance
Category Variants Paths

FGFR1 mutant FGFR1 act mut FGFR1 N546K

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Transcript NM_023110.3
gDNA chr8:g.38417331G>C
cDNA c.1638C>G
Protein p.N546K
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_023105 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716312 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_017013221.2 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
XM_006716312.2 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716311.1 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716311.1 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
NM_023110.3 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
XM_006716310 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716310.4 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716311 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716303.4 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
NM_001174066.1 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
NM_001174066.2 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716312.2 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716310.3 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716304.2 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
NM_001174066 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
NM_023105.3 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
NM_023110 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
XM_017013221 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
XM_017013221.1 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
XM_006716304 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
XM_006716303 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
NM_023105.2 chr8:g.38414851A>C c.1638T>G p.N546K RefSeq GRCh38/hg38
XM_006716303.3 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
XM_006716304.1 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38
NM_023110.2 chr8:g.38417331G>C c.1638C>G p.N546K RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 act mut Advanced Solid Tumor sensitive Zoligratinib Phase I Actionable In a Phase I trial, Debio 1347 (CH5183284) dosing regimen has been determined in solid tumor patients with activating FGFR1 alterations (JCO, Vol 33, No 15_suppl (May 20 Supplement), 2015: 2540). detail...
FGFR1 act mut central nervous system benign neoplasm predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase II trial (MATCH), Balversa (erdafitinib) was tolerated and resulted in a partial response (PR) in 10% (2/20) and stable disease (SD) in 30% (6/20) of heavily pre-treated pediatric patients with low-grade gliomas or glioneuronal tumors harboring activating mutations in FGFR1 (n=16), FGFR2 (n=1), FGFR4 (n=1), or FGFR1 fusions (n=2), with a 6-mo overall survival rate of 89.7%, 2 PR and 4 SD were observed in patients with FGFR1 mutations (J Clin Oncol 41, 2023 (suppl 16; abstr 10007); NCT03210714). detail...
FGFR1 act mut low grade glioma predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase II trial (MATCH), Balversa (erdafitinib) was tolerated and resulted in a partial response (PR) in 10% (2/20) and stable disease (SD) in 30% (6/20) of heavily pre-treated pediatric patients with low-grade gliomas or glioneuronal tumors harboring activating mutations in FGFR1 (n=16), FGFR2 (n=1), FGFR4 (n=1), or FGFR1 fusions (n=2), with a 6-mo overall survival rate of 89.7%, 2 PR and 4 SD were observed in patients with FGFR1 mutations ( (J Clin Oncol 41, 2023 (suppl 16; abstr 10007); NCT03210714). detail...
FGFR1 act mut Advanced Solid Tumor decreased response Nintedanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR1 demonstrated reduced sensitivity to Ofev (Nintedanib) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR1 act mut Advanced Solid Tumor decreased response Cediranib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR1 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
FGFR1 act mut transitional cell carcinoma no benefit Derazantinib Phase Ib/II Actionable In a Phase I/II trial (FIDES-02), Derazantinib (ARQ 087) treatment was well tolerated but demonstrated limited efficacy in patients with urothelial carcinoma harboring FGFR1 (n=4), FGFR2 (n=7), or FGFR3 (n=35) mutations or FGFR3 fusions (n=6), with an objective response rate of 8.2% (4/49, all partial responses) and disease control rate of 30.6% (15/49) by independent central review (PMID: 38627238; NCT04045613). 38627238
FGFR1 act mut Advanced Solid Tumor no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit receptor phosphorylation and cell proliferation in transformed cells expressing constitutively active FGFR1 in culture (PMID: 22238366). 22238366
FGFR1 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 FGFR1 in culture (PMID: 22238366). 22238366
FGFR1 act mut breast cancer sensitive FIIN-1 Preclinical Actionable In a preclinical study, FIIN-1 inhibited Fgfr1 activation-induced proliferation and transformation of human breast epithelial cell lines in culture (PMID: 20338520). 20338520
FGFR1 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
FGFR1 act mut Advanced Solid Tumor predicted - sensitive Erdafitinib Phase II Actionable In a Phase II trial (RAGNAR), Balversa (erdafitinib) treatment resulted in an objective response rate of 29.5% (64/217, 6 complete and 58 partial responses), a disease control rate of 74%, clinical benefit rate of 46%, a median duration of response of 6.9 months, median progression-free survival of 4.2 months, and median overall survival of 10.7 months in patients with advanced solid tumors harboring FGFR1, FGFR2, or FGFR3 mutations or fusions (PMID: 37541273; NCT04083976). 37541273
FGFR1 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 FGFR1 in culture (PMID: 22238366). 22238366
FGFR1 mutant Advanced Solid Tumor predicted - sensitive Zoligratinib 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
FGFR1 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...
FGFR1 mutant Advanced Solid Tumor predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase II trial (MATCH), Balversa (erdafitinib) treatment resulted in an objective response rate of 16% (4/25), median progression-free survival of 3.6 months, and median overall survival of 11.0 months in patients with advanced solid tumors harboring FGFR1, FGFR2, or FGFR3 mutations or fusions (PMID: 38603650; NCT02465060). 38603650
FGFR1 mutant transitional cell carcinoma predicted - sensitive Erdafitinib Phase II Actionable In a Phase II trial, Balversa (erdafitinib) treatment resulted in an objective response rate of 42% (40/96, 3 complete response, 37 partial response) and a disease control rate of 80% in patients with metastatic or unresectable urothelial carcinoma harboring FGFR alterations (J Clin Oncol 36, 2018 (suppl; abstr 4503); NCT02365597). detail...
FGFR1 mutant Advanced Solid Tumor sensitive Pemigatinib Preclinical - Cell line xenograft 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...