Gene Variant Detail

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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 confers a gain of function to the Fgfr3 protein as demonstrated by stabilized homodimer formation and constitutive phosphorylation in vitro (PMID: 17384684), constitutive ligand-independent cell proliferation in culture (PMID: 19381019, PMID: 29533785) and increased Akt signaling (PMID: 31316618).
Associated Drug Resistance Y

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Transcript NM_000142
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_011513422 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 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 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
XM_006713868 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 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_001163213 chr4:g.1801841C>G c.746C>G p.S249C RefSeq GRCh38/hg38

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Molecular Profile Protein Effect Treatment Approaches
FGFR3 S249C gain of function FGFR Inhibitor (Pan) FGFR3 Inhibitor
FGFR3 S249C FGFR3 over exp
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 bladder carcinoma sensitive R3Mab Preclinical - Cell line xenograft Actionable In a preclinical study, R3Mab 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 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 urinary system cancer sensitive BGJ398 Preclinical - Cell culture Actionable In a preclinical study, BGJ398 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 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 urinary system cancer sensitive AZD4547 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 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 Advanced Solid Tumor sensitive BGJ398 Preclinical - Cell culture Actionable In a preclinical study, BGJ398 inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770). 23786770
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 bladder urothelial carcinoma sensitive Dovitinib Phase II 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 Advanced Solid Tumor sensitive 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 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 sensitive Debio 1347 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 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 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 Advanced Solid Tumor sensitive R3Mab Preclinical - Cell culture Actionable In a preclinical study, R3Mab inhibited proliferation of transformed cells expressing FGFR3 S249C in culture (PMID: 19381019). 19381019
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 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 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 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