Gene Variant Detail

Transcript	gDNA	cDNA	Protein	Source Database	Genome Build
XM_006713868	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_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_011513422	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_006713873	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

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 system cancer	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Infigratinib (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	Advanced Solid Tumor	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Infigratinib (BGJ398) inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770).	23786770
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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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 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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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	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	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	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 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	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	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	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 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	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	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	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	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	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	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	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	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	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	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
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	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	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	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	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

Molecular Profile	Protein Effect	Treatment Approaches
FGFR3 S249C	gain of function	FGFR Inhibitor (Pan) FGFR3 Inhibitor
FGFR3 S249C FGFR3 over exp

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

Gene Variant Detail

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