[Paper-level Aggregated] PMCID: PMC6547681

Evidence Type(s): Functional

Summary: Mutation: G101V | Summary: The G101V mutation alters the molecular interaction of BCL-2 with venetoclax, affecting drug binding and contributing to resistance. It changes the interactions within the P2 pocket, impacting the positioning of venetoclax in relation to the BCL-2 structure. Additionally, it affects the binding affinity of the BCL-2 protein to the selective antagonist S55746, indicating a change in molecular function compared to the wild-type.

Evidence Type: Functional Mutation: E152 | Summary: The E152 mutation exhibits a rotamer change that influences the positioning of venetoclax, indicating an alteration in molecular function related to drug binding. It also alters the conformation and binding affinity of the BCL-2 protein, impacting its interaction with venetoclax. Furthermore, the E152 residue's rotamer configuration is altered in the BCL-2 G101V:S55746 structure, indicating a change in molecular function related to binding affinity.

Evidence Type: Functional Mutation: E152A | Summary: The E152A mutation restores venetoclax binding, indicating a functional alteration that can counteract the resistance caused by the G101V mutation. It maintains comparable binding to wild-type BCL-2 and restores high affinity for venetoclax when combined with G101V. The E152A double mutant also shows altered binding affinity to S55746, indicating a functional impact on molecular interactions.

Evidence Type: Functional Mutation: G101A | Summary: The G101A mutation introduces a milder bulk at the G101 position, which affects the interactions with venetoclax but maintains the overall positioning of the drug in the P4 pocket. It exhibits a binding affinity to venetoclax that is comparable to wild-type BCL-2, indicating a functional role in drug interaction.

Evidence Type: Functional Mutation: F104L | Summary: The F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function.

Evidence Type: Functional Mutation: F104 | Summary: The F104 residue plays a role in separating the P2 and P4 pockets of BCL-2, suggesting its importance in molecular function.

Gene→Variant (gene-first): BCL2(596):G101V BCL2(596):E152 BCL2(596):E152A BCL2(596):G101A BCL2(596):F104L BCL2(596):F104

Genes: BCL2(596)

Variants: G101V E152 E152A G101A F104L F104

[Paper-level Aggregated] PMCID: PMC6547681

Evidence Type(s): Oncogenic

Summary: Mutation: G101V | Summary: The G101V mutation in BCL-2 contributes to tumor progression by conferring resistance to therapy and altering drug binding characteristics, which may influence tumor development or progression.

Gene→Variant (gene-first): BCL2(596):G101V

Genes: BCL2(596)

Variants: G101V

[Paper-level Aggregated] PMCID: PMC6547681

Evidence Type(s): Predictive

Summary: Mutation: G101V | Summary: The G101V mutation is associated with acquired resistance to venetoclax therapy in patients with chronic lymphocytic leukaemia, indicating its predictive value for treatment response. It is linked to reduced affinity for venetoclax and a significantly higher LC50 concentration for the drug S55746, suggesting it may influence the response to this therapy.

Evidence Type: Predictive Mutation: F104L | Summary: The F104L mutation shows a significant change in venetoclax affinity, suggesting it may contribute to resistance against the drug.

Evidence Type: Predictive Mutation: F104C | Summary: The F104C mutation demonstrates altered venetoclax affinity, which implies a role in resistance to therapy.

Evidence Type: Predictive Mutation: E152 | Summary: The variant E152 is associated with venetoclax affinity, suggesting it may correlate with response or sensitivity to this specific therapy.

Gene→Variant (gene-first): BCL2(596):G101V BCL2(596):F104L BCL2(596):F104C BCL2(596):E152

Genes: BCL2(596)

Variants: G101V F104L F104C E152

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E152 | Summary: The E152 residue's rotamer configuration is altered in the BCL-2 G101V:S55746 structure, indicating a change in molecular function related to binding affinity. Evidence Type: Functional | Mutation: G101V | Summary: The G101V mutation affects the binding affinity of S55746, demonstrating a change in molecular function due to the variant. Evidence Type: Functional | Mutation: E152A | Summary: The E152A double mutant shows altered binding affinity to S55746, indicating a functional impact on molecular interactions.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

Genes: 596

Variants: E152 E152A G101V V101

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Predictive, Oncogenic

Summary: Evidence Type: Functional | Mutation: G101V | Summary: The G101V mutation alters the binding affinity of the BCL-2 protein to the selective antagonist S55746, indicating a change in molecular function compared to the wild-type. Evidence Type: Predictive | Mutation: G101V | Summary: The G101V mutation is associated with a significantly higher LC50 concentration for the drug S55746, suggesting that it may influence the response to this therapy. Evidence Type: Oncogenic | Mutation: G101V | Summary: The G101V mutation in BCL-2 is implicated in altering the drug binding characteristics, which may contribute to tumor development or progression.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: E152 | Summary: The E152 mutation alters the conformation and binding affinity of the BCL-2 protein, impacting its interaction with venetoclax. Evidence Type: Functional | Mutation: E152A | Summary: The E152A mutation maintains comparable binding to wild-type BCL-2 and restores high affinity for venetoclax when combined with G101V. Evidence Type: Functional | Mutation: G101A | Summary: The G101A mutation exhibits a binding affinity to venetoclax that is comparable to wild-type BCL-2, indicating a functional role in drug interaction. Evidence Type: Oncogenic | Mutation: G101V | Summary: The G101V mutation contributes to altered binding dynamics with venetoclax, suggesting a role in tumor development or progression through its impact on drug affinity.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101A 596:G101V

Genes: 596

Variants: E152 E152A G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive

Summary: Evidence Type: Predictive | Mutation: E152 | Summary: The variant E152 is associated with venetoclax affinity, suggesting it may correlate with response or sensitivity to this specific therapy.

Gene→Variant (gene-first): 596:E152

Genes: 596

Variants: E152

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive

Summary: Evidence Type: Predictive | Mutation: G101V | Summary: The G101V mutation is associated with reduced affinity for venetoclax, indicating a potential resistance to therapy. Evidence Type: Predictive | Mutation: F104L | Summary: The F104L mutation shows a significant change in venetoclax affinity, suggesting it may contribute to resistance against the drug. Evidence Type: Predictive | Mutation: F104C | Summary: The F104C mutation demonstrates altered venetoclax affinity, which implies a role in resistance to therapy.

Gene→Variant (gene-first): 596:F104C 596:F104L 596:G101V

Genes: 596

Variants: F104C F104L G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: F104L | Summary: The F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function. Evidence Type: Functional | Mutation: F104 | Summary: The F104 residue plays a role in separating the P2 and P4 pockets of BCL-2, suggesting its importance in molecular function.

Gene→Variant (gene-first): 596:F104 596:F104L 596:L104

Genes: 596

Variants: F104 F104L L104

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G101V | Summary: The G101V mutation alters drug binding by changing the interactions within the P2 pocket, affecting the positioning of venetoclax in relation to the BCL-2 structure. Evidence Type: Functional | Mutation: G101A | Summary: The G101A mutation introduces a milder bulk at the G101 position, which affects the interactions with venetoclax but maintains the overall positioning of the drug in the P4 pocket. Evidence Type: Functional | Mutation: E152 | Summary: The E152 mutation exhibits a rotamer change that influences the positioning of venetoclax, indicating an alteration in molecular function related to drug binding.

Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V

Genes: 596

Variants: E152 G101 G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 3

Evidence Type(s): None

Summary: Not enough information in this passage.

Gene→Variant (gene-first): 596:F104

Genes: 596

Variants: F104

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: G101V | Summary: The BCL-2 mutation G101V is associated with reduced affinity for venetoclax, indicating that it confers drug resistance in patients with chronic lymphocytic leukaemia. Evidence Type: Functional | Mutation: G101V | Summary: Biochemical analyses reveal that the G101V mutation alters the molecular interaction of BCL-2 with venetoclax, providing insight into the structural basis for drug resistance. Evidence Type: Oncogenic | Mutation: G101V | Summary: The G101V mutation in BCL-2 contributes to tumor progression by conferring resistance to therapy, which is a characteristic of oncogenic mutations.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: G101V | Summary: The G101V mutation is associated with acquired resistance to venetoclax therapy in patients with chronic lymphocytic leukaemia, indicating its predictive value for treatment response. Evidence Type: Functional | Mutation: G101V | Summary: The G101V mutation alters the molecular interaction of BCL-2 with venetoclax, affecting drug binding and contributing to resistance. Evidence Type: Functional | Mutation: E152 | Summary: The E152 residue is involved in the binding dynamics of venetoclax, with its interaction being affected by the G101V mutation. Evidence Type: Functional | Mutation: E152A | Summary: The E152A mutation restores venetoclax binding, indicating a functional alteration that can counteract the resistance caused by the G101V mutation. Evidence Type: Functional | Mutation: V101 | Summary: The V101 residue influences the binding of venetoclax through its interaction with the G101V mutation, highlighting its role in the functional dynamics of drug resistance.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

Genes: 596

Variants: E152 E152A G101V V101

[Paper-level Aggregated] PMCID: PMC6547681

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

Justification: Oncogenic: The G101V mutation in BCL-2 is associated with acquired resistance to venetoclax therapy in patients with chronic lymphocytic leukaemia, indicating its role in promoting cancer progression. Functional: The study describes how the G101V mutation alters the binding affinity of venetoclax to BCL-2, demonstrating a functional impact on drug interaction and resistance mechanisms. Predictive: The identification of the G101V mutation as a factor that reduces venetoclax affinity allows for predictions about patient responses to this therapy, suggesting that its presence may indicate a likelihood of treatment failure. Prognostic: The emergence of the G101V mutation in patients failing venetoclax therapy suggests it may serve as a prognostic marker for treatment outcomes in chronic lymphocytic leukaemia.

Gene→Variant (gene-first): BCL2(596):E152 BCL2(596):E152A BCL2(596):G101A BCL2(596):G101V BCL2(596):V101 BCL2(596):G101 BCL2(596):F104 BCL2(596):F104L BCL2(596):L104 BCL2(596):F104C

Genes: BCL2(596)

Variants: E152 E152A G101A G101V V101 G101 F104 F104L L104 F104C

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the BCL-2 protein to the drug S55746, indicating a change in molecular function related to drug interaction. Oncogenic: The G101V variant is implicated in the context of tumor development as it affects the binding of a therapeutic agent, suggesting its role in cancer progression.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

Genes: 596

Variants: E152 E152A G101V V101

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the drug S55746, indicating a change in molecular function related to drug interaction. Predictive: The variant G101V is associated with a change in response to the drug S55746, as indicated by the differences in binding affinity and LC50 concentrations, suggesting its role in treatment sensitivity.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the E152A mutation alters the binding affinity of the BCL-2 protein to venetoclax, indicating a change in molecular function related to protein binding. Predictive: The evidence suggests that the E152A mutation, when combined with G101V, restores high affinity binding to venetoclax, which implies a correlation with response to this specific therapy.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101A 596:G101V

Genes: 596

Variants: E152 E152A G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive

Justification: Predictive: The passage discusses the role of E152 in venetoclax affinity, indicating a correlation with response or sensitivity to the therapy.

Gene→Variant (gene-first): 596:E152

Genes: 596

Variants: E152

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how the BCL-2 mutants, including G101V, F104L, and F104C, exhibit varying affinities for venetoclax, indicating their role in providing resistance to therapy. Functional: The passage describes how the BCL-2 mutants maintain tight binding to BH3 domains, which alters their molecular function and contributes to their ability to prevent apoptosis.

Gene→Variant (gene-first): 596:F104C 596:F104L 596:G101V

Genes: 596

Variants: F104C F104L G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function related to the variant.

Gene→Variant (gene-first): 596:F104 596:F104L 596:L104

Genes: 596

Variants: F104 F104L L104

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the G101V mutation alters drug binding by changing the molecular interactions within the BCL-2 structure, indicating an alteration in biochemical function. Predictive: The evidence suggests that the G101V mutation impacts the binding affinity of venetoclax, which correlates with the response to this specific therapy.

Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V

Genes: 596

Variants: E152 G101 G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 3

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 596:F104

Genes: 596

Variants: F104

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Functional

Justification: Predictive: The variant G101V is associated with drug resistance to venetoclax in patients, indicating a correlation with treatment response. Functional: The passage discusses the biochemical analyses of the G101V mutant, revealing how it alters the affinity of venetoclax, which relates to its molecular function.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the emergence of the G101V mutation in patients failing therapy with venetoclax, indicating a correlation between the variant and resistance to this specific therapy. Functional: The passage describes how the G101V mutation alters the binding of venetoclax to BCL-2, indicating a change in molecular function related to drug resistance.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

Genes: 596

Variants: E152 E152A G101V V101

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the BCL-2 protein to the drug S55746, indicating a change in molecular function related to drug interaction. Oncogenic: The G101V variant is implicated in the context of tumor development as it affects the binding of a therapeutic agent, suggesting its role in cancer progression.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

Genes: 596

Variants: E152 E152A G101V V101

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the drug S55746, indicating a change in molecular function related to drug interaction. Predictive: The variant G101V is associated with a change in response to the drug S55746, as indicated by the differences in binding affinity and LC50 concentrations, suggesting its role in treatment sensitivity.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the E152A mutation alters the binding affinity of the BCL-2 protein to venetoclax, indicating a change in molecular function related to protein binding. Predictive: The evidence suggests that the E152A mutation, when combined with G101V, restores high affinity binding to venetoclax, which implies a correlation with response to this specific therapy.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101A 596:G101V

Genes: 596

Variants: E152 E152A G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive

Justification: Predictive: The passage discusses the role of E152 in venetoclax affinity, indicating a correlation with response or sensitivity to the therapy.

Gene→Variant (gene-first): 596:E152

Genes: 596

Variants: E152

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how the BCL-2 mutants, including G101V, F104L, and F104C, exhibit varying affinities for venetoclax, indicating their role in providing resistance to therapy. Functional: The passage describes how the BCL-2 mutants maintain tight binding to BH3 domains, which alters their molecular function and contributes to their ability to prevent apoptosis.

Gene→Variant (gene-first): 596:F104C 596:F104L 596:G101V

Genes: 596

Variants: F104C F104L G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function related to the variant.

Gene→Variant (gene-first): 596:F104 596:F104L 596:L104

Genes: 596

Variants: F104 F104L L104

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the G101V mutation alters drug binding by changing the molecular interactions within the BCL-2 structure, indicating an alteration in biochemical function. Predictive: The evidence suggests that the G101V mutation impacts the binding affinity of venetoclax, which correlates with the response to this specific therapy.

Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V

Genes: 596

Variants: E152 G101 G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 3

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 596:F104

Genes: 596

Variants: F104

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Functional

Justification: Predictive: The variant G101V is associated with drug resistance to venetoclax in patients, indicating a correlation with treatment response. Functional: The passage discusses the biochemical analyses of the G101V mutant, revealing how it alters the affinity of venetoclax, which relates to its molecular function.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the emergence of the G101V mutation in patients failing therapy with venetoclax, indicating a correlation between the variant and resistance to this specific therapy. Functional: The passage describes how the G101V mutation alters the binding of venetoclax to BCL-2, indicating a change in molecular function related to drug resistance.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

Genes: 596

Variants: E152 E152A G101V V101