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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_006713869 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
NM_001163213 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
XM_047449821.1 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
NM_000142.4 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_011513422.2 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_001354809.1 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_006713868 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_006713871.2 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_006713872 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
XM_006713868.1 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_006713868.2 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
NM_001354810.2 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_006713871.1 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_011513422.1 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_006713870.1 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_001163213.1 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
XM_006713870 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_006713871 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_006713873.1 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
XM_011513420.2 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

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 S249C FGFR3 over exp transitional cell carcinoma sensitive PD173074 Preclinical Actionable In a preclinical study, PD173074 inhibited growth of urothelial carcinoma (UC) cells expressing high levels of FGFR3 S249C, but had reduced efficacy against UC cells with low levels of FGFR3 S249C expression (PMID: 22869148). 22869148
FGFR3 S249C PIK3CA E545K transitional cell carcinoma sensitive Erdafitinib + Pictilisib Preclinical - Pdx & cell culture Actionable In a preclinical study, combination treatment with Balversa (erdafitinib) and Pictilisib (GDC-0941) resulted in synergistic inhibition of tumor growth in a patient-derived xenograft (PDX) model of urothelial cancer harboring FGFR3 S249C and PIK3CA E545K (PMID: 37377403). 37377403
FGFR3 S249C PIK3CA E545K bladder urothelial carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, PIK3CA E545K was identified in the post-progression biopsy of a patient with bladder urothelial cancer harboring FGFR3 S249C who progressed on treatment with Balversa (erdafitinib) (PMID: 37377403). 37377403
FGFR3 S249C PIK3CA E545K bladder urothelial carcinoma predicted - resistant Futibatinib Case Reports/Case Series Actionable In a clinical case study, a patient with bladder urothelial cancer harboring FGFR3 S249C and an acquired PIK3CA E545K experienced primary resistance to treatment with Lytgobi (futibatinib) (PMID: 37377403). 37377403
FGFR3 S249C PIK3CA E545A transitional cell carcinoma predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a clinical case study, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 5.8 months in a patient with upper tract urothelial carcinoma harboring FGFR3 S249C and PIK3CA E545A (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 N540K PIK3CA E545K transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 N540K was identified in the post-progression biopsy of a patient with upper tract urothelial carcinoma harboring FGFR3 S249C and PIK3CA E545K who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 V553L transitional cell carcinoma not predictive Pemigatinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V553L was identified in the post-progression biopsy of a patient with upper tract urothelial carcinoma harboring FGFR3 S249C who previously responded to Pemazyre (pemigatinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 V555L transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V555L was identified in the post-progression circulating tumor DNA of a patient with urothelial cancer harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 V555L transitional cell carcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-201), FGFR3 V555L was identified in post-progression biopsy in a patient with urothelial carcinoma harboring FGFR3 S249C who previously achieved stable disease on Pemazyre (pemigatinib) treatment (PMID: 37956738; NCT02872714). 37956738
FGFR3 S249C FGFR3 V553M bladder urothelial carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V553M was identified in the post-progression circulating tumor DNA of a patient with bladder urothelial cancer harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 amp PTEN C136fs transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, PTEN C136fs and FGFR3 amplification (6 copies) were identified in the tissue biopsy of a patient with bladder urothelial cancer harboring FGFR3 S249C who progressed on Balversa (erdafitinib) after 1.4 months of treatment (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 V553M FGFR3 V555L transitional cell carcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-201), FGFR3 V553M and V555L were identified in post-progression biopsy in a patient with urothelial carcinoma harboring FGFR3 S249C who previously achieved a partial response on Pemazyre (pemigatinib) treatment (PMID: 37956738; NCT02872714). 37956738
FGFR3 S249C FGFR3 M528I FGFR3 V553M transitional cell carcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-201), FGFR3 V553M and M528I were identified in post-progression biopsy in a patient with urothelial carcinoma harboring FGFR3 S249C who previously achieved a partial response on Pemazyre (pemigatinib) treatment (PMID: 37956738; NCT02872714). 37956738
FGFR3 S249C FGFR3 N540S transitional cell carcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a Phase II trial (FIGHT-201), FGFR3 N540S was identified in post-progression biopsy in a patient with urothelial carcinoma harboring FGFR3 S249C who previously achieved stable disease on Pemazyre (pemigatinib) treatment (PMID: 37956738; NCT02872714). 37956738
FGFR2 R255W FGFR3 S249C FGFR3 V553M FGFR3 K650M transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V553M, FGFR3 K650M, and FGFR2 R255W, along with AKT1 E17K, was identified on post-progression biopsy in a patient with urothelial carcinoma harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) (PMID: 37682528). 37682528