Gene Variant Detail

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Gene FGFR3
Variant N540S
Impact List missense
Protein Effect gain of function - predicted
Gene Variant Descriptions FGFR3 N540S lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). N540S results in increased Fgfr3 autophosphorylation in cell culture (PMID: 26992226), and therefore, is predicted to result in a gain of Fgfr3 protein function.
Associated Drug Resistance

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Transcript NM_000142
gDNA chr4:g.1805643A>G
cDNA c.1619A>G
Protein p.N540S
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
XM_006713870 chr4:g.1805634A>G c.1619A>G p.N540S RefSeq GRCh38/hg38
NM_000142 chr4:g.1805643A>G c.1619A>G p.N540S RefSeq GRCh38/hg38
XM_006713873 chr4:g.1805643A>G c.1619A>G p.N540S RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 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 7 patients with FGFR3 activating mutations (PMID: 32463741; NCT02465060). 32463741
FGFR3 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
FGFR3 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 FGFR3 in culture (PMID: 22238366). 22238366
FGFR3 act mut Advanced Solid Tumor decreased response Nintedanib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR3 demonstrated reduced sensitivity to Ofev (Nintedanib) in culture, when compared to other tyrosine kinase inhibitors (PMID: 22238366). 22238366
FGFR3 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 FGFR3 alterations (JCO, Vol 33, No 15_suppl (May 20 Supplement), 2015: 2540). detail...
FGFR3 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 FGFR3 in culture (PMID: 22238366). 22238366
FGFR3 act mut Advanced Solid Tumor decreased response Cediranib Preclinical Actionable In a preclinical study, transformed cells expressing constitutively active FGFR3 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
FGFR3 act mut urinary bladder cancer predicted - sensitive S-49076 Preclinical Actionable In a preclinical study, S-49076 inhibited autophosphorylation of FGFR3 and downstream signaling in bladder cancer cells over expressing constitutively active FGFR3 in culture (PMID: 23804704). 23804704
FGFR3 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 FGFR3 in culture (PMID: 22238366). 22238366
FGFR3 mutant transitional cell carcinoma sensitive Erdafitinib Phase I Actionable In a Phase I trial, Balversa (erdafitinib) treatment resulted in an objective response rate of 46% (12/26) in patients with urothelial carcinoma harboring FGFR genomic alterations, including 17 with FGFR3 mutations, and 11 with FGFR2 and/or FGFR3 fusions (PMID: 31088831; NCT01703481). 31088831
FGFR3 mutant transitional cell carcinoma sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase I trial, Balversa (erdafitinib) treatment resulted in 25% tumor shrinkage at week 8 in an urothelial cancer patient harboring FGFR3 mutations (PMID: 26324363; NCT01703481). 26324363
FGFR3 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...
FGFR3 mutant transitional cell carcinoma sensitive Erdafitinib Guideline Actionable Balversa (erdafitinib) is included in the guidelines for patients with advanced or metastatic urothelial carcinoma harboring Fgfr3 alterations after progression on platinum-based regimens (NCCN.org). detail...
FGFR3 mutant Advanced Solid Tumor sensitive Infigratinib Preclinical Actionable In a preclinical study, tumor cell lines with FGFR3 mutations demonstrated sensitivity to Infigratinib (BGJ398) in culture (PMID: 23002168). 23002168
FGFR3 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
FGFR3 mutant transitional cell carcinoma no benefit Nivolumab Phase II Actionable In a Phase II trial (CheckMate 275), Opdivo (nivolumab) (n=270) treatment resulted in similar response rate (20% vs 21%, p=0.2) in patients with FGFR3 mutant or wild-type metastatic transitional cell carcinoma (PMID: 31272788). 31272788
FGFR3 mutant transitional cell carcinoma predicted - sensitive Docetaxel + Vofatamab Phase Ib/II Actionable In a Phase I/II trial, Vofatamab (B-701) in combination with Taxotere (docetaxel) demonstrated safety and preliminary efficacy, resulted in enhanced activity in patients with locally advanced or metastatic urothelial carcinoma harboring FGFR3 mutations or fusions comparing to wild-type patients (Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 4534-4534; NCT02401542). detail...
FGFR3 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
FGFR3 mutant transitional cell carcinoma no benefit Atezolizumab Phase II Actionable In a Phase II trial (IMVigor 210, CheckMate 275), Tecentriq (atezolizumab) (n=119) treatment resulted in similar response rate (24% vs 21%, p=0.8) in patients with FGFR3 mutant or wild-type metastatic transitional cell carcinoma (PMID: 31272788). 31272788
FGFR3 mutant bladder urothelial carcinoma sensitive Dovitinib Phase II Actionable In a Phase II trial, Dovitinib (TKI258) treatment resulted in complete response in 33% (1/3) of patients with BCG-unresponsive, non-muscle-invasive, urothelial carcinoma of the bladder harboring FGFR3 mutations (PMID: 27932416). 27932416
FGFR3 mutant urinary bladder cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of bladder cancer cells harboring FGFR3 mutation in culture (PMID: 27550940). 27550940
FGFR3 mutant transitional cell carcinoma sensitive Infigratinib Clinical Study Actionable In a clinical study, Infigratinib (BGJ398) treatment in patients with FGFR3 alterations led to 25.4% (17/67) confirmed responses and a disease control rate of 64% (43/67), which included complete responses, partial responses, and stable disease, and resulted in a median progression-free survival of 3.75 months and a median overall survival of 7.75 months (PMID: 29848605). 29848605
FGFR3 mutant transitional cell carcinoma sensitive Infigratinib Phase I Actionable In a Phase I trial, Infigratinib (BGJ398) treatment resulted in complete response in 4% (1/25) and partial response in 32% (8/25) of urothelial carcinoma patients harboring FGFR3 mutations or fusions (J Clin Oncol 34, 2016 (suppl; abstr 4517); NCT01004224). detail...
FGFR3 mutant bladder urothelial carcinoma sensitive Erdafitinib Guideline Actionable Balversa (erdafitinib) is included in the guidelines for patients with advanced or metastatic urothelial carcinoma harboring Fgfr3 alterations after progression on platinum-based regimens (NCCN.org). detail...
FGFR3 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...
FGFR3 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...
FGFR3 mutant bladder urothelial carcinoma sensitive Infigratinib Phase I Actionable In a Phase I trial, patients with bladder urothelial carcinoma harboring an FGFR3 mutation demonstrated a disease control rate of 75% (6/8) when treated with Infigratinib (BGJ398), including 3 patients with a partial response and 3 with stable disease (PMID: 27870574; NCT01004224). 27870574
Molecular Profile Protein Effect Treatment Approaches
FGFR3 N540S gain of function - predicted FGFR Inhibitor (Pan) FGFR3 Inhibitor