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    1. karim2001khoury 19 Feb 2026
      Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use

      [Paper-level Aggregated] PMCID: PMC5029699

      Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

      Justification: Oncogenic: The text discusses several mutations in the FGFR3 gene that are frequently observed in cancer, particularly highlighting the activating mutations K650E and N540K, which are associated with increased kinase activity and cancer development. Functional: The evidence indicates that specific mutations, such as K650E and N540K, significantly enhance FGFR3 kinase activity, as demonstrated by increased auto-phosphorylation and substrate phosphorylation assays. Predictive: The text mentions that certain mutations, including N540K and K650E, affect the efficacy of FGFR inhibitors, suggesting that these mutations can predict responses to targeted therapies in clinical settings. Prognostic: The presence of specific mutations in FGFR3, such as K650E and N540K, is associated with distinct changes in drug efficacy, which may have implications for patient outcomes and treatment strategies in cancer therapy.

      Gene→Variant (gene-first): FGFR3(2261):D617 FGFR3(2261):D617G FGFR3(2261):G to W FGFR1(2260):G637 FGFR1(2260):G637W FGFR2(2263):E466K FGFR3(2261):R669 FGFR1(2260):D641 FGFR1(2260):L630 FGFR1(2260):V561 FGFR1(2260):D641G FGFR1(2260):D641N FGFR3(2261):V555 FGFR3(2261):V555M FGFR3(2261):G697 FGFR3(2261):G697C FGFR3(2261):K650 FGFR3(2261):N540 FGFR3(2261):K650E FGFR3(2261):N540K FGFR3(2261):H650 FGFR1(2260):R675 FGFR1(2260):R675G FGFR2(2263):Y653 FGFR2(2263):I538 FGFR2(2263):I538V FGFR3(2261):N540S FGFR3(2261):R669G FGFR3(2261):K650N FGFR3(2261):R669Q FGFR1(2260):R to G FGFR1(2260):V561M

      Genes: FGFR3(2261) FGFR1(2260) FGFR2(2263)

      Variants: D617 D617G G to W G637 G637W E466K R669 D641 L630 V561 D641G D641N V555 V555M G697 G697C K650 N540 K650E N540K H650 R675 R675G Y653 I538 I538V N540S R669G K650N R669Q R to G V561M

      CIViC paper-level aggregated PMC5029699
    2. karim2001khoury 19 Feb 2026
      Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the imp

      [Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the impact of FGFR3 kinase domain variants on drug responses and highlights the distinct changes in efficacy of inhibitors based on specific activating mutations, indicating a correlation with treatment response. Oncogenic: The mention of FGFR3 variants as drivers in diverse tumors suggests that these somatic mutations contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G

      Genes: 2261

      Variants: K650E N540K R669G

      CIViC paragraph-level PMC5029699 Predictive Oncogenic
    3. karim2001khoury 19 Feb 2026
      Some of the differences between the effects of tested inhibitors on activating FGFR variants (Figure 6) are consistent with observations from structural studies. Based on the crystal structure of FGFR1 KD V561M, the inte

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.

      Gene→Variant (gene-first): 2261:V555M 2260:V561M

      Genes: 2261 2260

      Variants: V555M V561M

      CIViC paragraph-level PMC5029699 Predictive Functional
    4. karim2001khoury 19 Feb 2026
      We further compared the effect of the two most potent FGFR-specific inhibitors AZD4547 and JNJ42756493 on hotspot mutations K650E and N540K in NIH3T3 cell lines. As previously reported and shown in Supplementary Figure S

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effect of the K650E and N540K variants on the efficacy of FGFR-specific inhibitors, indicating a correlation with treatment response. Oncogenic: The variants K650E and N540K are discussed in the context of their impact on cellular transformation and response to inhibitors, suggesting their role in tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E 2261:N540K

      Genes: 2261

      Variants: K650E N540K

      CIViC paragraph-level PMC5029699 Predictive Oncogenic
    5. karim2001khoury 19 Feb 2026
      The impact of each mutation on drug binding is expressed as a fold-difference in Ki compared to the FGFR3 KD WT (Figure 6C). Highly activating R669G and, in particular, hotspot mutation K650E had moderate effects on the

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.

      Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M

      Genes: 2263 2261

      Variants: I538 I538V K650E N540 N540K N540S R669G V555M

      CIViC paragraph-level PMC5029699 Predictive Functional
    6. karim2001khoury 19 Feb 2026
      We performed measurements of Ki for AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534 using purified FGFR3 KD WT and variants R669G, K650E, N540S, N540K, V555M and I538V (Figure 6, Supplementary Table S3). Ki values for

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.

      Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M

      Genes: 2263 2261

      Variants: I538V K650E N540K N540S R669G V555M

      CIViC paragraph-level PMC5029699 Predictive Functional
    7. karim2001khoury 19 Feb 2026
      It is well established that some acquired mutations in protein kinases greatly reduce drug binding; the best-illustrated examples are gatekeeper mutations also described in FGFR3 (V555M). The question of how primary muta

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses how mutations in protein kinases, such as V555M, can affect drug binding and implies a relationship between these mutations and drug efficacy, indicating a potential impact on treatment response. Oncogenic: The mention of V555M as an acquired mutation in FGFR3 suggests its role in tumor development or progression, particularly in the context of drug resistance.

      Gene→Variant (gene-first): 2261:V555M

      Genes: 2261

      Variants: V555M

      CIViC paragraph-level PMC5029699 Predictive Oncogenic
    8. karim2001khoury 19 Feb 2026
      JNJ42756493 occupies the ATP-binding cleft of FGFR1 largely as expected on the basis of previous complexes between FGFR1 and other type-I inhibitors (e. g. BJG-398, AZD4547, PD173074 and TKI258) and where the activation

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.

      Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561

      Genes: 2260

      Variants: D641 L630 V561

      CIViC paragraph-level PMC5029699 Functional
    9. karim2001khoury 19 Feb 2026
      Previous structural studies of FGFR2 KD highlighted a long-range allosteric communication linking the kinase hinge, the alphaC-helix and the A-loop. It was also illustrated that some A-loop mutations (such as FGFR3 K650E

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G

      Genes: 2261 2260

      Variants: K650E R669G R675 R675G

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    10. karim2001khoury 19 Feb 2026
      To gain further insight into the activation mechanism of the R669G mutation in FGFR3, we performed NMR studies in which we compared the backbone amide chemical shift perturbations (CSPs) associated with the R669G mutatio

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.

      Gene→Variant (gene-first): 2261:R669G

      Genes: 2261

      Variants: R669G

      CIViC paragraph-level PMC5029699 Functional
    11. karim2001khoury 19 Feb 2026
      Comparison of this new FGFR1 R675G KD structure (Figure 4C, top) with inactive (apo) FGFR1 KD (PDB: 4UWY) and active, FGFR1-3P (pdb 3GQI) (Figure 4C, bottom) structures shows that FGFR1 R675G KD differs from the inactive

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional

      Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.

      Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653

      Genes: 2261 2260 2263

      Variants: H650 R675 R675G Y653

      CIViC paragraph-level PMC5029699 Functional
    12. karim2001khoury 19 Feb 2026
      The residue corresponding to R669 in FGFR3 is conserved and also mutated in all other FGFRs in cancer as well as in FGFR2 in bone dysplasia (Supplementary Table S1). To assess the mechanism that underpins activation, we

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.

      Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G

      Genes: 2260 2261

      Variants: R to G R669 R675G

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    13. karim2001khoury 19 Feb 2026
      Activation mechanism of FGFR3 R669G mutation

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.

      Gene→Variant (gene-first): 2261:R669G

      Genes: 2261

      Variants: R669G

      CIViC paragraph-level PMC5029699 Functional
    14. karim2001khoury 19 Feb 2026
      Comparison of our experimental data (Figure 2) with the assessments obtained using bioinformatics tools (Supplementary Table S1B and S1C) suggests that considering multiple methods together can provide insight into the i

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.

      Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669

      Genes: 2261 2263 2260

      Variants: D617G E466K G637W R669

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    15. karim2001khoury 19 Feb 2026
      Analysis of the FGFR3 R669G NIH3T3 cell line has shown that despite low expression levels, downstream signaling appeared to be enhanced as well as FGFR3 phosphorylation (Figure 4A).

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.

      Gene→Variant (gene-first): 2261:R669G

      Genes: 2261

      Variants: R669G

      CIViC paragraph-level PMC5029699 Functional
    16. karim2001khoury 19 Feb 2026
      It could be expected that some mutations that map to the KD do not affect kinase activity directly as measured under conditions in vitro. In particular, the hotspot G697C mutation which does not have an effect in such as

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.

      Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K

      Genes: 2261

      Variants: G697C K650E N540K

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    17. karim2001khoury 19 Feb 2026
      From these direct measurements of kinase activity it seems that a considerable number of mutations reported so far result in kinase activation to some degree and that replacements that cause activation are not limited to

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E

      Genes: 2261

      Variants: K650E

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    18. karim2001khoury 19 Feb 2026
      Two mutations, D617G and G637W, completely abolished kinase activity (Figure 2A and 2B, bottom panel). Both residues are strongly conserved among protein kinases and some of the replacements of these residues in various

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.

      Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W

      Genes: 2261 2260

      Variants: D617 D617G G to W G637 G637W

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    19. karim2001khoury 19 Feb 2026
      Twelve out of 26 analyzed mutations had very little or no effect on FGFR3 KD activity (Figure 2A and 2B, bottom panel). The number of observations in cancer for most of these mutations is low with the exception of G697C

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.

      Gene→Variant (gene-first): 2261:G697C

      Genes: 2261

      Variants: G697C

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    20. karim2001khoury 19 Feb 2026
      Several other mutations, including V555M, D641G and D641N resulted in an increase of auto-phosphorylation up to 7-fold (Figure 2A) and a similar increase in substrate phosphorylation (Figure 2B, middle panel). The V555M

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.

      Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M

      Genes: 2260 2261

      Variants: D641G D641N V555 V555M

      CIViC paragraph-level PMC5029699 Predictive Functional
    21. karim2001khoury 19 Feb 2026
      Isolated FGFR KDs undergo auto-phosphorylation on several tyrosine residues and this property correlates well with the kinase activity towards natural and synthetic substrates. We used purified proteins of 26 FGFR3 KD va

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.

      Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q

      Genes: 2263 2261

      Variants: I538V K650E K650N N540K N540S R669G R669Q

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    22. karim2001khoury 19 Feb 2026
      The number of cancer mutations in FGFR KDs that have been comprehensively assessed for their functional impact is limited, with the most emphasis being on replacements at positions corresponding to FGFR3 K650 and mutatio

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.

      Gene→Variant (gene-first): 2261:K650 2261:N540K

      Genes: 2261

      Variants: K650 N540K

      CIViC paragraph-level PMC5029699 Functional
    23. karim2001khoury 19 Feb 2026
      A number of crystal structures of FGFR KD in non-phosphorylated and phosphorylated forms have been reported. The 3D-structures highlighted the features that undergo substantial changes and play a key role in the activati

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.

      Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669

      Genes: 2263 2261

      Variants: I538 K650 N540 R669

      CIViC paragraph-level PMC5029699 Oncogenic
    24. karim2001khoury 19 Feb 2026
      Comparison of positions mutated in bone dysplasia in all FGFRs with those reported for FGFR3 in cancer (Figure 1B, bottom) highlighted common residues including I538, N540, K650 and R669. With respect to the secondary st

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669

      Genes: 2261 2263

      Variants: G697 I538 K650 N540 R669

      CIViC paragraph-level PMC5029699
    25. karim2001khoury 19 Feb 2026
      It has been previously highlighted that a number of cancer mutations, in particular in FGFR2 and FGFR3, have also been described in various developmental syndromes such as bone dysplasia. Positions mutated in FGFR3 in th

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K

      Genes: 2261

      Variants: K650 N540 N540K

      CIViC paragraph-level PMC5029699 Diagnostic Oncogenic
    26. karim2001khoury 19 Feb 2026
      The intracellular portion (residues 397-806 for FGFR3) comprises the juxtamembrane region, KD and C-terminal regions. The number of observed mutations at each residue within the intracellular portion of FGFR3 was compile

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.

      Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540

      Genes: 2261

      Variants: G697 G697C K650 N540

      CIViC paragraph-level PMC5029699 Oncogenic Functional
    27. karim2001khoury 19 Feb 2026
      Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the imp

      [Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the impact of FGFR3 kinase domain variants on drug responses and highlights the distinct changes in efficacy of inhibitors based on specific activating mutations, indicating a correlation with treatment response. Oncogenic: The mention of FGFR3 variants as drivers in diverse tumors suggests that these somatic mutations contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G

      Genes: 2261

      Variants: K650E N540K R669G

      CIViC paragraph-level PMC5029699 Predictive Oncogenic
    28. karim2001khoury 19 Feb 2026
      Some of the differences between the effects of tested inhibitors on activating FGFR variants (Figure 6) are consistent with observations from structural studies. Based on the crystal structure of FGFR1 KD V561M, the inte

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.

      Gene→Variant (gene-first): 2261:V555M 2260:V561M

      Genes: 2261 2260

      Variants: V555M V561M

      CIViC paragraph-level PMC5029699 Predictive Functional
    29. karim2001khoury 19 Feb 2026
      We further compared the effect of the two most potent FGFR-specific inhibitors AZD4547 and JNJ42756493 on hotspot mutations K650E and N540K in NIH3T3 cell lines. As previously reported and shown in Supplementary Figure S

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effect of the K650E and N540K variants on the efficacy of FGFR-specific inhibitors, indicating a correlation with treatment response. Oncogenic: The variants K650E and N540K are discussed in the context of their impact on cellular transformation and response to inhibitors, suggesting their role in tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E 2261:N540K

      Genes: 2261

      Variants: K650E N540K

      CIViC paragraph-level PMC5029699 Predictive Oncogenic
    30. karim2001khoury 19 Feb 2026
      The impact of each mutation on drug binding is expressed as a fold-difference in Ki compared to the FGFR3 KD WT (Figure 6C). Highly activating R669G and, in particular, hotspot mutation K650E had moderate effects on the

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.

      Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M

      Genes: 2263 2261

      Variants: I538 I538V K650E N540 N540K N540S R669G V555M

      CIViC paragraph-level PMC5029699 Predictive Functional
    31. karim2001khoury 19 Feb 2026
      We performed measurements of Ki for AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534 using purified FGFR3 KD WT and variants R669G, K650E, N540S, N540K, V555M and I538V (Figure 6, Supplementary Table S3). Ki values for

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.

      Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M

      Genes: 2263 2261

      Variants: I538V K650E N540K N540S R669G V555M

      CIViC paragraph-level PMC5029699 Predictive Functional
    32. karim2001khoury 19 Feb 2026
      It is well established that some acquired mutations in protein kinases greatly reduce drug binding; the best-illustrated examples are gatekeeper mutations also described in FGFR3 (V555M). The question of how primary muta

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses how mutations in protein kinases, such as V555M, can affect drug binding and implies a relationship between these mutations and drug efficacy, indicating a potential impact on treatment response. Oncogenic: The mention of V555M as an acquired mutation in FGFR3 suggests its role in tumor development or progression, particularly in the context of drug resistance.

      Gene→Variant (gene-first): 2261:V555M

      Genes: 2261

      Variants: V555M

      CIViC paragraph-level PMC5029699 Predictive Oncogenic
    33. karim2001khoury 19 Feb 2026
      JNJ42756493 occupies the ATP-binding cleft of FGFR1 largely as expected on the basis of previous complexes between FGFR1 and other type-I inhibitors (e. g. BJG-398, AZD4547, PD173074 and TKI258) and where the activation

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.

      Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561

      Genes: 2260

      Variants: D641 L630 V561

      CIViC paragraph-level PMC5029699 Functional
    34. karim2001khoury 19 Feb 2026
      Previous structural studies of FGFR2 KD highlighted a long-range allosteric communication linking the kinase hinge, the alphaC-helix and the A-loop. It was also illustrated that some A-loop mutations (such as FGFR3 K650E

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G

      Genes: 2261 2260

      Variants: K650E R669G R675 R675G

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    35. karim2001khoury 19 Feb 2026
      To gain further insight into the activation mechanism of the R669G mutation in FGFR3, we performed NMR studies in which we compared the backbone amide chemical shift perturbations (CSPs) associated with the R669G mutatio

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.

      Gene→Variant (gene-first): 2261:R669G

      Genes: 2261

      Variants: R669G

      CIViC paragraph-level PMC5029699 Functional
    36. karim2001khoury 19 Feb 2026
      Comparison of this new FGFR1 R675G KD structure (Figure 4C, top) with inactive (apo) FGFR1 KD (PDB: 4UWY) and active, FGFR1-3P (pdb 3GQI) (Figure 4C, bottom) structures shows that FGFR1 R675G KD differs from the inactive

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional

      Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.

      Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653

      Genes: 2261 2260 2263

      Variants: H650 R675 R675G Y653

      CIViC paragraph-level PMC5029699 Functional
    37. karim2001khoury 19 Feb 2026
      The residue corresponding to R669 in FGFR3 is conserved and also mutated in all other FGFRs in cancer as well as in FGFR2 in bone dysplasia (Supplementary Table S1). To assess the mechanism that underpins activation, we

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.

      Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G

      Genes: 2260 2261

      Variants: R to G R669 R675G

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    38. karim2001khoury 19 Feb 2026
      Activation mechanism of FGFR3 R669G mutation

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.

      Gene→Variant (gene-first): 2261:R669G

      Genes: 2261

      Variants: R669G

      CIViC paragraph-level PMC5029699 Functional
    39. karim2001khoury 19 Feb 2026
      Comparison of our experimental data (Figure 2) with the assessments obtained using bioinformatics tools (Supplementary Table S1B and S1C) suggests that considering multiple methods together can provide insight into the i

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.

      Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669

      Genes: 2261 2263 2260

      Variants: D617G E466K G637W R669

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    40. karim2001khoury 19 Feb 2026
      Analysis of the FGFR3 R669G NIH3T3 cell line has shown that despite low expression levels, downstream signaling appeared to be enhanced as well as FGFR3 phosphorylation (Figure 4A).

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.

      Gene→Variant (gene-first): 2261:R669G

      Genes: 2261

      Variants: R669G

      CIViC paragraph-level PMC5029699 Functional
    41. karim2001khoury 19 Feb 2026
      It could be expected that some mutations that map to the KD do not affect kinase activity directly as measured under conditions in vitro. In particular, the hotspot G697C mutation which does not have an effect in such as

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.

      Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K

      Genes: 2261

      Variants: G697C K650E N540K

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    42. karim2001khoury 19 Feb 2026
      From these direct measurements of kinase activity it seems that a considerable number of mutations reported so far result in kinase activation to some degree and that replacements that cause activation are not limited to

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.

      Gene→Variant (gene-first): 2261:K650E

      Genes: 2261

      Variants: K650E

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    43. karim2001khoury 19 Feb 2026
      Two mutations, D617G and G637W, completely abolished kinase activity (Figure 2A and 2B, bottom panel). Both residues are strongly conserved among protein kinases and some of the replacements of these residues in various

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.

      Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W

      Genes: 2261 2260

      Variants: D617 D617G G to W G637 G637W

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    44. karim2001khoury 19 Feb 2026
      Twelve out of 26 analyzed mutations had very little or no effect on FGFR3 KD activity (Figure 2A and 2B, bottom panel). The number of observations in cancer for most of these mutations is low with the exception of G697C

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.

      Gene→Variant (gene-first): 2261:G697C

      Genes: 2261

      Variants: G697C

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    45. karim2001khoury 19 Feb 2026
      Several other mutations, including V555M, D641G and D641N resulted in an increase of auto-phosphorylation up to 7-fold (Figure 2A) and a similar increase in substrate phosphorylation (Figure 2B, middle panel). The V555M

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.

      Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M

      Genes: 2260 2261

      Variants: D641G D641N V555 V555M

      CIViC paragraph-level PMC5029699 Predictive Functional
    46. karim2001khoury 19 Feb 2026
      Isolated FGFR KDs undergo auto-phosphorylation on several tyrosine residues and this property correlates well with the kinase activity towards natural and synthetic substrates. We used purified proteins of 26 FGFR3 KD va

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.

      Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q

      Genes: 2263 2261

      Variants: I538V K650E K650N N540K N540S R669G R669Q

      CIViC paragraph-level PMC5029699 Functional Oncogenic
    47. karim2001khoury 19 Feb 2026
      The number of cancer mutations in FGFR KDs that have been comprehensively assessed for their functional impact is limited, with the most emphasis being on replacements at positions corresponding to FGFR3 K650 and mutatio

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.

      Gene→Variant (gene-first): 2261:K650 2261:N540K

      Genes: 2261

      Variants: K650 N540K

      CIViC paragraph-level PMC5029699 Functional
    48. karim2001khoury 19 Feb 2026
      A number of crystal structures of FGFR KD in non-phosphorylated and phosphorylated forms have been reported. The 3D-structures highlighted the features that undergo substantial changes and play a key role in the activati

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.

      Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669

      Genes: 2263 2261

      Variants: I538 K650 N540 R669

      CIViC paragraph-level PMC5029699 Oncogenic
    49. karim2001khoury 19 Feb 2026
      Comparison of positions mutated in bone dysplasia in all FGFRs with those reported for FGFR3 in cancer (Figure 1B, bottom) highlighted common residues including I538, N540, K650 and R669. With respect to the secondary st

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669

      Genes: 2261 2263

      Variants: G697 I538 K650 N540 R669

      CIViC paragraph-level PMC5029699
    50. karim2001khoury 19 Feb 2026
      It has been previously highlighted that a number of cancer mutations, in particular in FGFR2 and FGFR3, have also been described in various developmental syndromes such as bone dysplasia. Positions mutated in FGFR3 in th

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K

      Genes: 2261

      Variants: K650 N540 N540K

      CIViC paragraph-level PMC5029699 Diagnostic Oncogenic
    51. karim2001khoury 19 Feb 2026
      The intracellular portion (residues 397-806 for FGFR3) comprises the juxtamembrane region, KD and C-terminal regions. The number of observed mutations at each residue within the intracellular portion of FGFR3 was compile

      [Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.

      Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540

      Genes: 2261

      Variants: G697 G697C K650 N540

      CIViC paragraph-level PMC5029699 Oncogenic Functional
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