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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_000142.5 |
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 |
---|---|---|---|---|---|
NM_001163213.2 | 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 | 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_006713873.1 | 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 |
XM_006713871.1 | 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_001163213 | 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 |
NM_001354810.1 | 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_006713868 | 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 |
NM_022965.4 | 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 |
NM_022965 | 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_047449821.1 | 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 |
XM_006713870.2 | 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_001354809.1 | 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_047449823.1 | 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_011513420.1 | 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 |
XM_047449824.1 | 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 |
XM_006713873 | 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 |
NM_022965.3 | 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_006713871 | 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_011513422.2 | 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 |
XM_006713868.2 | 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 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 |