[Paper-level Aggregated] PMCID: PMC11551396

Evidence Type(s): Functional

Summary: Mutation: N771insSVD | Summary: The N771insSVD variant alters the molecular function of EGFR, as it is involved in drug sensitivity and resistance mechanisms compared to wild-type EGFR.

Evidence Type: Functional Mutation: L858R | Summary: The L858R mutation alters the enzyme kinetic parameters of EGFR, demonstrating a significant increase in catalytic efficiency compared to wild-type EGFR.

Evidence Type: Functional Mutation: T790M | Summary: The T790M mutation is associated with altered enzyme kinetics, showing increased catalytic rates compared to wild-type EGFR, and is also studied in the context of cocrystal structures with various inhibitors, indicating an alteration in molecular or biochemical function.

Evidence Type: Functional Mutation: V948R | Summary: The V948R mutation is associated with altered molecular or biochemical function as it is studied in the context of cocrystal structures with various inhibitors.

Evidence Type: Functional Mutation: C797 | Summary: The C797 mutation forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding.

Gene→Variant (gene-first): EGFR(1956):N771insSVD EGFR(1956):L858R EGFR(1956):T790M EGFR(1956):V948R EGFR(1956):C797

Genes: EGFR(1956)

Variants: N771insSVD L858R T790M V948R C797

[Paper-level Aggregated] PMCID: PMC11551396

Evidence Type(s): Oncogenic

Summary: Mutation: L858R | Summary: The L858R mutation contributes to tumor development or progression, as indicated by its enhanced catalytic rates and sensitivity compared to other variants, and is associated with enhanced sensitivity to inhibitors compared to wild-type EGFR.

Evidence Type: Oncogenic Mutation: T790 | Summary: The T790 mutation is associated with tumor development or progression, as it is a gatekeeper residue involved in resistance mechanisms and is linked to the binding of TAK-788, indicating its role through interaction with therapeutic agents.

Evidence Type: Oncogenic Mutation: T790M | Summary: The T790M mutation is associated with an inactive kinase conformation, contributing to tumor development or progression.

Evidence Type: Oncogenic Mutation: V948R | Summary: The V948R mutation prevents the formation of the activating asymmetric dimer interaction, indicating its role in tumor development or progression.

Gene→Variant (gene-first): EGFR(1956):L858R EGFR(1956):T790 EGFR(1956):T790M EGFR(1956):V948R

Genes: EGFR(1956)

Variants: L858R T790 T790M V948R

[Paper-level Aggregated] PMCID: PMC11551396

Evidence Type(s): Predictive

Summary: Mutation: L858R | Summary: The L858R mutation is associated with a lack of sensitivity to 1st-3rd generation EGFR tyrosine kinase inhibitors (TKIs) and shows a drug-sensitizing effect, correlating with greater potency against L858R EGFR compared to wild-type EGFR. It is evaluated for its response to a diverse panel of EGFR inhibitors, indicating its potential role in predicting treatment sensitivity or resistance.

Evidence Type: Predictive Mutation: N771insSVD | Summary: The N771insSVD variant shows a lack of sensitivity to 1st-3rd generation EGFR TKIs, suggesting its predictive role in therapy response.

Evidence Type: Predictive Mutation: T790M | Summary: The T790M mutation is included in the evaluation of biochemical potencies against EGFR inhibitors, suggesting its relevance in predicting treatment response or resistance.

Gene→Variant (gene-first): EGFR(1956):L858R EGFR(1956):N771insSVD EGFR(1956):T790M

Genes: EGFR(1956)

Variants: L858R N771insSVD T790M

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: C797 | Summary: The mutation C797 is involved in forming a covalent bond with an inhibitor, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: T790 | Summary: The mutation T790 is described in the context of its interaction with a quinoline substituent, suggesting it alters molecular or biochemical function.

Gene→Variant (gene-first): 1956:C797 1956:T790

Genes: 1956

Variants: C797 T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: T790 | Summary: The T790 mutation is associated with the binding of TAK-788, indicating its role in tumor development or progression through its interaction with therapeutic agents.

Gene→Variant (gene-first): 1956:T790

Genes: 1956

Variants: T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: C797 | Summary: The C797 mutation forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Evidence Type: Oncogenic | Mutation: T790M | Summary: The T790M mutation is associated with an inactive kinase conformation, contributing to tumor development or progression. Evidence Type: Oncogenic | Mutation: V948R | Summary: The V948R mutation prevents the formation of the activating asymmetric dimer interaction, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R

Genes: 1956

Variants: C797 T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 15

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: T790 | Summary: The T790 mutation is mentioned in the context of its interaction with inhibitors, suggesting its role in tumor development or progression as it is a gatekeeper residue involved in resistance mechanisms.

Gene→Variant (gene-first): 1956:T790

Genes: 1956

Variants: T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T790M | Summary: The T790M mutation is associated with altered molecular or biochemical function as it is studied in the context of cocrystal structures with various inhibitors. Evidence Type: Functional | Mutation: V948R | Summary: The V948R mutation is associated with altered molecular or biochemical function as it is studied in the context of cocrystal structures with various inhibitors.

Gene→Variant (gene-first): 1956:T790M 1956:V948R

Genes: 1956

Variants: T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: L858R | Summary: The L858R mutation shows a drug-sensitizing effect, correlating with greater potency against L858R EGFR compared to WT EGFR, indicating its relevance in therapy response. Evidence Type: Oncogenic | Mutation: L858R | Summary: The L858R mutation contributes to tumor development or progression, as it is associated with enhanced sensitivity to inhibitors compared to wild-type EGFR.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive

Summary: Evidence Type: Predictive | Mutation: L858R | Summary: The L858R mutation is evaluated for its response to a diverse panel of EGFR inhibitors, indicating its potential role in predicting treatment sensitivity or resistance. Evidence Type: Predictive | Mutation: T790M | Summary: The T790M mutation is included in the evaluation of biochemical potencies against EGFR inhibitors, suggesting its relevance in predicting treatment response or resistance.

Gene→Variant (gene-first): 1956:L858R 1956:T790M

Genes: 1956

Variants: L858R T790M

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: L858R | Summary: The L858R mutation is associated with enhanced inhibitor sensitivity due to its decreased affinity for ATP, which correlates with treatment response to EGFR TKIs. Evidence Type: Oncogenic | Mutation: L858R | Summary: The L858R mutation contributes to tumor development or progression, as indicated by its enhanced catalytic rates and sensitivity compared to other variants.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L858R | Summary: The L858R mutation alters the enzyme kinetic parameters of EGFR, demonstrating a significant increase in catalytic efficiency compared to wild-type EGFR. Evidence Type: Functional | Mutation: T790M | Summary: The T790M mutation is associated with altered enzyme kinetics, showing increased catalytic rates compared to wild-type EGFR. Evidence Type: Functional | Mutation: Glu4 | Summary: The Glu4 mutation is evaluated in terms of its impact on enzyme kinetics, indicating a functional alteration in comparison to wild-type EGFR.

Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M

Genes: 7294 1956

Variants: Glu4 L858R T790M

[Paragraph-level] PMCID: PMC11551396 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: L858R | Summary: The L858R variant is associated with a lack of sensitivity to 1st-3rd generation EGFR tyrosine kinase inhibitors (TKIs), indicating its predictive role in therapy response. Evidence Type: Predictive | Mutation: N771insSVD | Summary: The N771insSVD variant shows a lack of sensitivity to 1st-3rd generation EGFR TKIs, suggesting its predictive role in therapy response. Evidence Type: Functional | Mutation: N771insSVD | Summary: The N771insSVD variant alters the molecular function of EGFR, as it is involved in drug sensitivity and resistance mechanisms compared to wild-type EGFR.

Gene→Variant (gene-first): 1956:L858R 1956:N771insSVD

Genes: 1956

Variants: L858R N771insSVD

[Paper-level Aggregated] PMCID: PMC11551396

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text indicates that the exon 20 insertion variants (insASV and insSVD) exhibit enhanced catalytic rates and lower Km values compared to WT EGFR, suggesting their role in promoting cancer through increased activity. Predictive: The study evaluates the sensitivity of various EGFR mutations, including L858R and exon 20 insertions, to different inhibitors, indicating that the presence of specific mutations can predict the effectiveness of targeted therapies. Functional: The biochemical analysis of the variants, including kinetic studies and enzyme assays, demonstrates their functional characteristics, such as catalytic efficiency and inhibitor sensitivity, which are critical for understanding their role in cancer biology.

Gene→Variant (gene-first): EGFR(1956):C797 EGFR(1956):T790 EGFR(1956):T790M EGFR(1956):V948R TXK(7294):Glu4 EGFR(1956):L858R EGFR(1956):N771insSVD

Genes: EGFR(1956) TXK(7294)

Variants: C797 T790 T790M V948R Glu4 L858R N771insSVD

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant C797 interacts with the inhibitor at a molecular level, specifically forming covalent bonds and influencing the binding interactions within the kinase structure.

Gene→Variant (gene-first): 1956:C797 1956:T790

Genes: 1956

Variants: C797 T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.

Gene→Variant (gene-first): 1956:T790

Genes: 1956

Variants: T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C797 variant forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Oncogenic: The T790M and V948R variants are described in the context of adopting an inactive kinase conformation, which suggests their role in tumor progression or development.

Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R

Genes: 1956

Variants: C797 T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 15

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1956:T790

Genes: 1956

Variants: T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1956:T790M 1956:V948R

Genes: 1956

Variants: T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation between the L858R variant and drug sensitivity, indicating that the L858R mutation has a drug-sensitizing effect, which aligns with predictive evidence regarding therapy response. Oncogenic: The L858R variant is implicated in greater potency against EGFR compared to WT EGFR, suggesting its role in tumor development or progression, which is characteristic of oncogenic evidence.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.

Gene→Variant (gene-first): 1956:L858R 1956:T790M

Genes: 1956

Variants: L858R T790M

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the enhanced inhibitor sensitivity of the L858R variant in relation to its decreased affinity for ATP, indicating a correlation with sensitivity to EGFR TKIs, which aligns with predictive evidence. Oncogenic: The passage implies that the L858R variant contributes to oncogenicity, as it discusses the variant's biochemical properties and their relation to tumor development and progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.

Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M

Genes: 7294 1956

Variants: Glu4 L858R T790M

[Paragraph-level] PMCID: PMC11551396 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the drug sensitivity and resistance of the exon 20 insertion variants, indicating their correlation with response to specific therapies, particularly EGFR tyrosine kinase inhibitors. Oncogenic: The passage describes somatic mutations in the EGFR gene, specifically the exon 20 insertion variants, which contribute to tumor development in non-small cell lung cancer.

Gene→Variant (gene-first): 1956:L858R 1956:N771insSVD

Genes: 1956

Variants: L858R N771insSVD

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant C797 interacts with the inhibitor at a molecular level, specifically forming covalent bonds and influencing the binding interactions within the kinase structure.

Gene→Variant (gene-first): 1956:C797 1956:T790

Genes: 1956

Variants: C797 T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.

Gene→Variant (gene-first): 1956:T790

Genes: 1956

Variants: T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C797 variant forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Oncogenic: The T790M and V948R variants are described in the context of adopting an inactive kinase conformation, which suggests their role in tumor progression or development.

Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R

Genes: 1956

Variants: C797 T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 15

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1956:T790

Genes: 1956

Variants: T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1956:T790M 1956:V948R

Genes: 1956

Variants: T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation between the L858R variant and drug sensitivity, indicating that the L858R mutation has a drug-sensitizing effect, which aligns with predictive evidence regarding therapy response. Oncogenic: The L858R variant is implicated in greater potency against EGFR compared to WT EGFR, suggesting its role in tumor development or progression, which is characteristic of oncogenic evidence.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.

Gene→Variant (gene-first): 1956:L858R 1956:T790M

Genes: 1956

Variants: L858R T790M

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the enhanced inhibitor sensitivity of the L858R variant in relation to its decreased affinity for ATP, indicating a correlation with sensitivity to EGFR TKIs, which aligns with predictive evidence. Oncogenic: The passage implies that the L858R variant contributes to oncogenicity, as it discusses the variant's biochemical properties and their relation to tumor development and progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.

Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M

Genes: 7294 1956

Variants: Glu4 L858R T790M

[Paragraph-level] PMCID: PMC11551396 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the drug sensitivity and resistance of the exon 20 insertion variants, indicating their correlation with response to specific therapies, particularly EGFR tyrosine kinase inhibitors. Oncogenic: The passage describes somatic mutations in the EGFR gene, specifically the exon 20 insertion variants, which contribute to tumor development in non-small cell lung cancer.

Gene→Variant (gene-first): 1956:L858R 1956:N771insSVD

Genes: 1956

Variants: L858R N771insSVD