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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 |
Transcript | NM_000142.4 |
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 | 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_011513420 | 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_001163213.1 | 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_011513420.1 | 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 |
NM_001354810.1 | 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_001163213 | 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_006713873 | 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_006713869.1 | 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_022965.3 | 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_006713868.1 | 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_011513422 | 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 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
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 | 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 | 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 | 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 | 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 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 | 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 | 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 | 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 | 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 | 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 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | renal pelvis transitional cell carcinoma | predicted - sensitive | AZD4547 | 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 FGFR2 S249C (PMID: 32463741; NCT02465060). | 32463741 |
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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 |