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Gene FGFR3
Variant S249C
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions FGFR3 S249C lies within the linker region between IgD2 and IgD3 of the Fgfr3 protein (PMID: 19381019). S249C results in stabilized homodimer formation and constitutive Fgfr3 phosphorylation in vitro (PMID: 17384684), ligand-independent cell proliferation in culture (PMID: 19381019, PMID: 29533785), increased Akt signaling (PMID: 31316618), a growth advantage relative to wild-type Fgfr3 in a competition assay, and increased transformation activity in cultured cells (PMID: 34272467).
Associated Drug Resistance Y
Category Variants Paths

FGFR3 mutant FGFR3 act mut FGFR3 S249C

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Transcript NM_000142.5
gDNA chr4:g.1801841C>G
cDNA c.746C>G
Protein p.S249C
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
XM_006713870.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713869.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713868.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713873.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_001163213.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_047449821.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713868.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_022965 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_047449820.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713873.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713871 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_022965.4 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713869.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_011513422.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_047449823.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_011513420 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_001354810.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_001354810.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713871.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_047449824.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_047449822.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_011513422.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_022965.3 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_011513420.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713872 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_011513422 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_001163213.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_001354809.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713869 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_000142.4 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713871.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713868 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_000142.5 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_000142 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_011513420.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713873 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713870.2 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_001354809.1 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
XM_006713870 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38
NM_001163213 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 S249C urinary system cancer sensitive Fexagratinib Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4547 decreased Myc expression and inhibited growth of a urinary tract cancer cell line harboring FGFR3 S249C in culture and in xenograft models (PMID: 27401245). 27401245
FGFR3 S249C renal pelvis transitional cell carcinoma predicted - sensitive Fexagratinib Case Reports/Case Series 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%, including stable disease for greater than 6 months in a patient with transitional cell carcinoma of the renal pelvis harboring FGFR3 S249C (PMID: 32463741; NCT02465060). 32463741
FGFR3 S249C urinary system cancer sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased Myc expression, induced cell cycle arrest, and inhibited growth of a urinary tract cancer cell line harboring FGFR3 S249C in culture (PMID: 27401245). 27401245
FGFR3 S249C Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased viability of a cell line expressing FGFR3 S249C in culture (PMID: 32370101). 32370101
FGFR3 S249C Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770). 23786770
FGFR3 S249C Advanced Solid Tumor resistant Dasatinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing FGFR3 S249C was resistant to Sprycel (dasatinib) treatment in culture (PMID: 32370101). 32370101
FGFR3 S249C bladder urothelial carcinoma sensitive Dovitinib Case Reports/Case Series Actionable In a Phase II trial, Dovitinib (TKI258) treatment resulted in complete response in a patient with BCG-unresponsive, non-muscle-invasive, urothelial carcinoma of the bladder harboring FGFR3 S249C (PMID: 27932416). 27932416
FGFR3 S249C urinary bladder cancer sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited cell proliferation in bladder cancer cells harboring FGFR3 S249C mutation in culture (PMID: 22238366). 22238366
FGFR3 S249C Advanced Solid Tumor conflicting Dovitinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR3 S249C were resistant to treatment with Dovitinib (TKI258) in culture (PMID: 34272467). 34272467
FGFR3 S249C Advanced Solid Tumor conflicting Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770). 23786770
FGFR3 S249C urinary bladder cancer resistant Nintedanib Preclinical Actionable In a preclinical study, bladder cancer cells harboring FGFR3 S249C were resistant to Ofev (Nintedanib) induced inhibition of cell proliferation in culture (PMID: 22238366). 22238366
FGFR3 S249C renal pelvis transitional cell carcinoma predicted - sensitive Pazopanib Clinical Study Actionable In a case study, a patient with urothelial carcinoma of the renal pelvis harboring FGFR3 S249C demonstrated a partial response lasting 9 months following treatment with Votrient (pazopanib) (PMID: 27271022). 27271022
FGFR3 S249C urinary bladder cancer sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of bladder cancer cells harboring FGFR3 S249C in culture and in cell line xenograft models (PMID: 22238366). 22238366
FGFR3 S249C Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770). 23786770
FGFR3 S249C renal pelvis transitional cell carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, renal pelvis transitional cell carcinoma cells harboring FGFR3 S249C were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
FGFR3 S249C renal pelvis transitional cell carcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, renal pelvis transitional cell carcinoma cells harboring FGFR3 S249C were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR3 S249C urinary bladder cancer no benefit Brivanib Preclinical Actionable In a preclinical study, Brivanib (BMS-540215) did not inhibit growth of bladder cancer cells harboring FGFR3 S249C in culture (PMID: 22238366). 22238366
FGFR3 S249C urinary bladder cancer sensitive Cediranib Preclinical Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of bladder cancer cells harboring FGFR3 S249C mutation in culture (PMID: 22238366). 22238366
FGFR3 S249C urinary bladder cancer sensitive Zoligratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Debio 1347 inhibited proliferation of bladder cancer cells harboring FGFR3 S249C in culture and inhibited tumor growth in FGFR3 S249C-positive bladder cancer cell line xenograft models (PMID: 25169980). 25169980
FGFR3 S249C ovarian cancer predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase II trial (RAGNAR), treatment with Balversa (erdafitinib) resulted in a partial response with a duration of response of 5.55 months in a patient with ovarian cancer harboring FGFR3 S249C (PMID: 37541273; NCT04083976). 37541273
FGFR3 S249C transitional cell carcinoma sensitive Erdafitinib Guideline Actionable Balversa (erdafitinib) is included in guidelines for patients with advanced urothelial carcinoma who have received chemotherapy and an immune checkpoint inhibitor and harboring select FGFR mutations including FGFR3 S249C (PMID: 38490358; ESMO.org). 38490358 detail...
FGFR3 S249C transitional cell carcinoma sensitive Erdafitinib FDA approved - On 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 and FGFR3 S249C is included in the companion diagnostic (PMID: 31340094; NCT02365597). detail... 31340094 detail...
FGFR3 S249C lung squamous cell carcinoma predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase II trial (RAGNAR), treatment with Balversa (erdafitinib) resulted in a partial response with a duration of response of 9.03 months in a patient with squamous non-small cell lung cancer harboring FGFR3 S249C (PMID: 37541273; NCT04083976). 37541273
FGFR3 S249C bladder urothelial carcinoma sensitive Erdafitinib Guideline Actionable Balversa (erdafitinib) is included in guidelines for patients with advanced bladder urothelial carcinoma who have received chemotherapy and an immune checkpoint inhibitor and harboring select FGFR mutations including FGFR3 S249C (PMID: 38490358; ESMO.org). 38490358 detail...
FGFR3 S249C bladder urothelial carcinoma sensitive Erdafitinib FDA approved - On 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 and FGFR3 S249C is included in the companion diagnostic (PMID: 31340094; NCT02365597). detail... 31340094 detail...
FGFR3 S249C malignant ovarian Brenner 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 FGFR1-3 mutations or fusions, including a partial response in a patient with malignant Brenner tumor of the ovary harboring FGFR3 S249C (PMID: 38603650; NCT02465060). 38603650
FGFR3 S249C head and neck squamous cell carcinoma predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a Phase II trial (RAGNAR), treatment with Balversa (erdafitinib) resulted in a partial response with a duration of response of 2.89 months in a patient with squamous cell head and neck cancer harboring FGFR3 S249C (PMID: 37541273; NCT04083976). 37541273
FGFR3 S249C urinary bladder cancer sensitive Erdafitinib Phase II Actionable In a Phase II trial (THOR-2), Balversa (erdafitinib) improved median recurrence-free survival (not reached vs 11.6 mo, HR=0.28, p=0.0008) in patients with recurrent high risk non-muscle invasive bladder cancer harboring FGFR3 mutations such as S249C (n=31), R248C (n=4), G370C, (n=3) or Y373C (n=10) or FGFR2-BICC1 (n=1), FGFR3-BAIAP2L1 (n=1), or FGFR3-TACC3 (n=5) compared to intravesical chemotherapy (PMID: 37871701; NCT04172675). 37871701
FGFR3 S249C transitional cell carcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Lytgobi (futibatinib) treatment led to an overall objective response rate of 15.8% (3/19, 3 partial responses) and a disease control rate of 47.4% (9/19), with stable disease in 6, in urothelial cancer patients harboring an FGFR3 mutation or FGFR1 mutation, including partial responses in 2 patients with urothelial cancer harboring FGFR3 S249C with a progression-free survival of 2.7 and 4.7 mo, and a duration of response of 1.4 and 3.4 mo, respectively (PMID: 34551969; NCT02052778). 34551969
FGFR3 S249C renal pelvis transitional cell carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, renal pelvis transitional cell carcinoma cells harboring FGFR3 S249C were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR3 S249C bladder carcinoma sensitive Vofatamab Preclinical - Cell line xenograft Actionable In a preclinical study, Vofatamab (B-701) decreased dimer formation and constitutive activation of FGFR3 S249C, and inhibited growth of bladder cancer cell lines harboring FGFR3 S249C in culture and in xenograft models (PMID: 19381019). 19381019
FGFR3 S249C Advanced Solid Tumor sensitive Vofatamab Preclinical - Cell culture Actionable In a preclinical study, Vofatamab (B-701) inhibited proliferation of transformed cells expressing FGFR3 S249C in culture (PMID: 19381019). 19381019
FGFR3 S249C urinary bladder cancer resistant PD173074 Preclinical - Cell culture Actionable In a preclinical study, bladder cancer cells harboring FGFR3 S249C were resistant to PD173074 in culture (PMID: 23558953). 23558953
FGFR3 S249C urinary bladder cancer sensitive ASP5878 Preclinical - Cell line xenograft Actionable In a preclinical study, ASP5878 treatment inhibited proliferation of a bladder cancer cell line harboring FGFR3 S249C in culture, and resulted in tumor regression in xenograft models (Mol Cancer Ther December 2015 14; A170). detail...
FGFR3 S249C transitional cell carcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a clinical case study, Pemazyre (pemigatinib) treatment resulted in a partial response with a progression-free survival of 8.3 months in a patient with urothelial cancer harboring FGFR3 S249C (PMID: 37377403). 37377403
FGFR3 S249C transitional cell carcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), Pemazyre (pemigatinib) treatment led to a partial response in a urothelial cancer patient harboring FGFR3 S249C (PMID: 35176457; NCT02393248). 35176457
FGFR3 S249C transitional cell carcinoma predicted - sensitive Pemigatinib Phase II Actionable In a Phase II trial (FIGHT-201), Pemazyre (pemigatinib) treatment resulted in an objective response rate (ORR) of 17.9% with continuous dosing and 24.2% with intermittent dosing in patients with urothelial carcinoma harboring FGFR3 mutations, with an ORR in patients harboring FGFR3 S249C of 23.9% with continuous dosing (n=46) and 24.6% with intermittent dosing (n=61) (PMID: 37956738; NCT02872714). 37956738
FGFR3 S249C bladder urothelial carcinoma predicted - sensitive Pembrolizumab + Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), treatment with the combination of Pemazyre (pemigatinib) and Keytruda (pembrolizumab) demonstrated safety in patients with advanced solid tumors and resulted in an objective response rate of 26.9% (7/26, all partial responses), including a partial response with a duration of response of 50.3 months in a patient with urothelial bladder cancer harboring FGFR3 S249C (PMID: 38986210; NCT02393248). 38986210
FGFR3 S249C Advanced Solid Tumor predicted - resistant E7090 Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR3 S249C were resistant to treatment with E7090 in culture (PMID: 34272467). 34272467
FGFR3 S249C urinary bladder cancer predicted - sensitive Cisplatin + Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, the addition of Ipatasertib (GDC0068) treatment resulted in enhanced sensitivity of bladder cancer cells expressing FGFR3 S249C to treatment with Platinol (cisplatin) in culture, demonstrating a greater reduction in cell proliferation and increased apoptotic activity when compared to Platinol (cisplatin) alone (PMID: 31316618). 31316618
FGFR3 S249C urinary bladder cancer predicted - sensitive Cisplatin + LY294002 Preclinical - Cell culture Actionable In a preclinical study, the addition of LY294002 treatment resulted in enhanced sensitivity of bladder cancer cells expressing FGFR3 S249C to treatment with Platinol (cisplatin) in culture, demonstrating a greater reduction in cell proliferation and increased apoptotic activity when compared to Platinol (cisplatin) alone (PMID: 31316618). 31316618
FGFR3 S249C bladder carcinoma sensitive CPL304110 Preclinical - Cell culture Actionable In a preclinical study, CPL304110 treatment inhibited proliferation of a bladder carcinoma cell line harboring FGFR3 S249C in culture (PMID: 33199155). 33199155
FGFR3 S249C urinary bladder cancer sensitive CPL304110 Preclinical - Cell line xenograft Actionable In a preclinical study, CPL304110 inhibited Erk phosphorylation in a bladder cancer cell line harboring FGFR3 S249C in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38282676). 38282676
FGFR3 S249C transitional cell carcinoma sensitive Erdafitinib + Gefitinib Preclinical - Pdx & cell culture Actionable In a preclinical study, combination treatment with Balversa (erdafitinib) and Iressa (gefitinib) inhibited cell growth of patient-derived urothelial cancer cells harboring FGFR3 S249C and PIK3CA E545A in culture, and led to synergistic inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 37377403). 37377403
FGFR3 S249C urinary bladder cancer sensitive 3D185 Preclinical - Cell culture Actionable In a preclinical study, 3D185 inhibited downstream signaling and proliferation in a bladder cancer cell line harboring FGFR3 S249C in culture (PMID: 31438996). 31438996
FGFR3 S249C urinary bladder cancer sensitive Erdafitinib + Quisinostat Preclinical - Cell culture Actionable In a preclinical study, the combination of Balversa (erdafitinib) and Quisinostat (JNJ-26481585) synergistically inhibited viability in a bladder cancer cell line harboring FGFR3 S249C in culture (PMID: 37479885). 37479885
FGFR3 S249C urinary bladder cancer predicted - sensitive TYRA-300 Preclinical - Cell line xenograft Actionable In a preclinical study, TYRA-300 induced tumor regression a cell line xenograft model of bladder cancer harboring FGFR3 S249C (Annals of Oncology 33 (2022): S751). detail...
FGFR3 S249C adult spinal cord glioblastoma multiforme predicted - sensitive Anlotinib + Irinotecan Case Reports/Case Series Actionable In a clinical case study, Anlotinib (AL-3818) and Camptosar (irinotecan) combination treatment resulted in symptom improvement and a partial response maintained for at least 10 months in a patient with IDH wild-type primary spinal cord glioblastoma harboring FGFR3 S249C (PMID: 35847381). 35847381
FGFR3 S249C Advanced Solid Tumor sensitive Dasatinib + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Sprycel (dasatinib) treatment inhibited viability of a cell line expressing FGFR3 S249C in culture (PMID: 32370101). 32370101
FGFR3 S249C lung squamous cell carcinoma sensitive R3-altibody Preclinical - Pdx Actionable In a preclinical study, R3-altibody inhibited tumor growth in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring FGFR3 S249C (PMID: 39082679). 39082679
FGFR3 S249C bladder urothelial carcinoma sensitive R3-altibody Preclinical - Cell line xenograft Actionable In a preclinical study, R3-altibody inhibited Fgfr3 dimerization and proliferation in a urothelial carcinoma cell line harboring FGFR3 S249C in culture and induced tumor regression in a cell line xenograft model (PMID: 39082679). 39082679
FGFR3 S249C Advanced Solid Tumor sensitive R3-altibody Preclinical - Cell culture Actionable In a preclinical study, R3-altibody inhibited Fgfr3 dimerization and downstream signaling and decreased proliferation in a cell line expressing FGFR3 S249C in culture (PMID: 39082679). 39082679