[Paper-level Aggregated] PMCID: PMC9837058

Evidence Type(s): Functional

Summary: Mutation: D915N | Summary: The D915N mutation is described as a kinase dead mutation that does not cause significant changes in protein conformation or membrane binding, indicating its role in altering molecular function without affecting these properties.

Evidence Type: Functional Mutation: N345K | Summary: The N345K mutation in p110alpha is associated with altered membrane binding properties, as evidenced by HDX-MS experiments showing protection in specific regions of the protein when interacting with membranes, indicating a change in molecular function related to membrane association.

Evidence Type: Functional Mutation: E726K | Summary: The E726K mutation alters molecular or biochemical function, particularly in relation to the disengagement of the ABD and p85 from the catalytic core, suggesting conformational changes associated with this mutation.

Evidence Type: Functional Mutation: H1047R | Summary: The H1047R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. It is associated with alterations in molecular or biochemical function, as indicated by the analysis of perturbations in conformation observed in HDX-MS experiments, and shows unique differences in binding interactions upon pY binding.

Evidence Type: Functional Mutation: His1047 | Summary: His1047 is involved in extensive interactions within the kinase domain, indicating that it plays a role in the molecular function of the protein.

Evidence Type: Functional Mutation: Met1043 | Summary: Met1043 is mentioned as a hydrophobic residue that contributes to the structural integrity of the kinase domain, suggesting its role in the molecular function of the protein.

Evidence Type: Functional Mutation: G1049R | Summary: The G1049R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. It shows significantly increased ATPase activity compared to wild type, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: M1043L | Summary: The M1043L mutation alters molecular function by increasing basal ATPase activity with a limited effect on membrane binding. It demonstrates significantly increased ATPase activity compared to wild type and is described in the context of kinase activity.

Evidence Type: Functional Mutation: N1068fs | Summary: The N1068fs mutation alters molecular function by increasing membrane binding without affecting basal ATPase activity and is described in the context of being a kinase dead variant.

Gene→Variant (gene-first): PIK3CA(5290):D915N PIK3CA(5290):N345K PIK3CA(5290):E726K PIK3CA(5290):H1047R PIK3CA(5290):His1047 PIK3CA(5290):Met1043 PIK3CA(5290):G1049R PIK3CA(5290):M1043L PIK3CA(5290):N1068fs

Genes: PIK3CA(5290)

Variants: D915N N345K E726K H1047R His1047 Met1043 G1049R M1043L N1068fs

[Paper-level Aggregated] PMCID: PMC9837058

Evidence Type(s): Oncogenic

Summary: Mutation: N345K | Summary: The N345K mutation is associated with increased membrane binding for oncogenic mutants, suggesting it contributes to tumor development or progression.

Evidence Type: Oncogenic Mutation: G106V | Summary: The G106V mutation is linked to increased membrane binding for oncogenic mutants, indicating its role in tumor development or progression.

Evidence Type: Oncogenic Mutation: G118D | Summary: The G118D mutation is associated with increased membrane binding for oncogenic mutants, suggesting it contributes to tumor development or progression.

Evidence Type: Oncogenic Mutation: E726K | Summary: The mutation E726K is mentioned in the context of oncogenic mutations, indicating its potential contribution to tumor development or progression, as it is part of a comparison with other missense oncogenic mutations.

Evidence Type: Oncogenic Mutation: H1047R | Summary: The H1047R mutation is described as an oncogenic mutation that contributes to tumor development by increasing membrane binding through alterations in the kinase domain structure. It also activates p110alpha, contributing to tumor development or progression by leading to activation through disruption of the inhibitory conformation of the C-terminal tail. H1047R/L is identified as the most frequent oncogenic mutation, contributing to tumor development or progression.

Evidence Type: Oncogenic Mutation: M1043L/I | Summary: M1043L/I is a frequent missense mutation that is associated with oncogenic behavior in tumor samples and is mentioned as activating p110alpha, suggesting its involvement in tumor development or progression.

Evidence Type: Oncogenic Mutation: G1049R | Summary: G1049R is noted as a frequent missense mutation that contributes to tumor development or progression. It activates p110alpha through distinct mechanisms, indicating its role in tumor development or progression, and contributes to tumor development by leading to activation through disruption of the inhibitory conformation of the C-terminal tail.

Evidence Type: Oncogenic Mutation: N1068fs | Summary: N1068fs is an activating frameshift variant that alters the C-terminus and is associated with oncogenic behavior in tumor samples.

Gene→Variant (gene-first): PIK3CA(5290):N345K PIK3CA(5290):G106V PIK3CA(5290):G118D PIK3CA(5290):E726K PIK3CA(5290):H1047R PIK3CA(5290):M1043L/I PIK3CA(5290):G1049R PIK3CA(5290):N1068fs

Genes: PIK3CA(5290)

Variants: N345K G106V G118D E726K H1047R M1043L/I G1049R N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: G1049R | Summary: The G1049R mutation is described as activating p110alpha through distinct mechanisms, indicating its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation is noted to activate p110alpha, contributing to tumor development or progression. Evidence Type: Oncogenic | Mutation: M1043I/L | Summary: The M1043I/L mutations are mentioned as activating p110alpha, which suggests their involvement in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043I/L

Genes: 5290

Variants: G1049R H1047R M1043I/L

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation shows unique differences in binding interactions upon pY binding, suggesting alterations in molecular function related to the regulatory motif of the protein.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 18

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation contributes to tumor development by leading to activation through disruption of the inhibitory conformation of the C-terminal tail. Evidence Type: Oncogenic | Mutation: G1049R | Summary: The G1049R mutation contributes to tumor development by leading to activation through disruption of the inhibitory conformation of the C-terminal tail.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation is associated with alterations in molecular or biochemical function, as indicated by the analysis of perturbations in conformation observed in the HDX-MS experiments.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: M1043L | Summary: The M1043L mutation alters molecular or biochemical function as it is described in the context of kinase activity. Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation alters molecular or biochemical function as it is described in the context of kinase activity. Evidence Type: Functional | Mutation: G1049R | Summary: The G1049R mutation alters molecular or biochemical function as it is described in the context of kinase activity. Evidence Type: Functional | Mutation: N1068fs | Summary: The N1068fs mutation alters molecular or biochemical function as it is described in the context of being a kinase dead variant.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. Evidence Type: Functional | Mutation: G1049R | Summary: The G1049R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. Evidence Type: Functional | Mutation: N1068fs | Summary: The N1068fs mutation alters molecular function by increasing membrane binding without affecting basal ATPase activity. Evidence Type: Functional | Mutation: M1043L | Summary: The M1043L mutation alters molecular function by increasing basal ATPase activity with a limited effect on membrane binding.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G1049R | Summary: The G1049R mutation shows significantly increased ATPase activity compared to wild type, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation exhibits significantly increased ATPase activity compared to wild type, suggesting a change in molecular function. Evidence Type: Functional | Mutation: M1043L | Summary: The M1043L mutation demonstrates significantly increased ATPase activity compared to wild type, reflecting an alteration in molecular function.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: H1047R/L | Summary: H1047R/L is identified as the most frequent oncogenic mutation, contributing to tumor development or progression. Evidence Type: Oncogenic | Mutation: M1043L/I | Summary: M1043L/I is a frequent missense mutation that is associated with oncogenic behavior in tumor samples. Evidence Type: Oncogenic | Mutation: G1049R | Summary: G1049R is noted as a frequent missense mutation that contributes to tumor development or progression. Evidence Type: Oncogenic | Mutation: N1068fs | Summary: N1068fs is an activating frameshift variant that alters the C-terminus and is associated with oncogenic behavior in tumor samples.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:H1047R/L 5290:M1043L 5290:M1043L/I 5290:N1044K 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation is described as an oncogenic mutation that contributes to tumor development by increasing membrane binding through alterations in the kinase domain structure. Evidence Type: Functional | Mutation: His1047 | Summary: His1047 is involved in extensive interactions within the kinase domain, indicating that it plays a role in the molecular function of the protein. Evidence Type: Functional | Mutation: Met1043 | Summary: Met1043 is mentioned as a hydrophobic residue that contributes to the structural integrity of the kinase domain, suggesting its role in the molecular function of the protein.

Gene→Variant (gene-first): 5290:H1047R 5290:His1047 5290:Met1043

Genes: 5290

Variants: H1047R His1047 Met1043

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: E726K | Summary: The mutation E726K is mentioned in the context of oncogenic mutations, indicating its potential contribution to tumor development or progression, as it is part of a comparison with other missense oncogenic mutations. Evidence Type: Functional | Mutation: E726K | Summary: The passage discusses conformational changes associated with the E726K mutation, suggesting that it alters molecular or biochemical function, particularly in relation to the disengagement of the ABD and p85 from the catalytic core.

Gene→Variant (gene-first): 5290:E726K

Genes: 5290

Variants: E726K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: N345K | Summary: The N345K mutation in p110alpha is associated with altered membrane binding properties, as evidenced by HDX-MS experiments showing protection in specific regions of the protein when interacting with membranes. This indicates a change in molecular function related to membrane association.

Gene→Variant (gene-first): 5290:N345K

Genes: 5290

Variants: N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: N345K | Summary: The N345K mutation is associated with increased membrane binding for oncogenic mutants, suggesting it contributes to tumor development or progression. Evidence Type: Oncogenic | Mutation: G106V | Summary: The G106V mutation is linked to increased membrane binding for oncogenic mutants, indicating its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: G118D | Summary: The G118D mutation is associated with increased membrane binding for oncogenic mutants, suggesting it contributes to tumor development or progression.

Gene→Variant (gene-first): 5290:G106V 5290:G118D 5290:N345K

Genes: 5290

Variants: G106V G118D N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D915N | Summary: The D915N mutation is described as a kinase dead mutation that does not cause significant changes in protein conformation or membrane binding, indicating its role in altering molecular function without affecting these properties.

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

[Paper-level Aggregated] PMCID: PMC9837058

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The text discusses multiple mutations (e.g., H1047R, G1049R, M1043L, N1068fs) that are frequently observed in cancer and describes their role in activating the PI3K pathway, indicating their oncogenic potential. Functional: The evidence describes how specific mutations (H1047R, G1049R, M1043L) lead to increased ATPase activity and enhanced membrane binding, demonstrating their functional impact on the PI3K enzyme activity. Predictive: The identification of specific mutations associated with increased membrane binding and PI3K activity suggests that these mutations could be used to predict the behavior of tumors and their response to therapies targeting the PI3K pathway.

Gene→Variant (gene-first): PIK3CA(5290):D915N PIK3CA(5290):E726K PIK3CA(5290):G1049R PIK3CA(5290):H1047R PIK3CA(5290):H1047R/L PIK3CA(5290):M1043L PIK3CA(5290):M1043L/I PIK3CA(5290):N1044K PIK3CA(5290):N1068fs PIK3CA(5290):M1043I/L PIK3CA(5290):G106V PIK3CA(5290):G118D PIK3CA(5290):N345K PIK3CA(5290):His1047 PIK3CA(5290):Met1043

Genes: PIK3CA(5290)

Variants: D915N E726K G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs M1043I/L G106V G118D N345K His1047 Met1043

[Paragraph-level] PMCID: PMC9837058 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how mutations in PIK3CA, including G1049R, H1047R, and M1043I/L, contribute to the activation of the PI3K pathway, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the conformation and binding properties of the p110alpha subunit, indicating that these variants affect molecular function related to PI3K activation.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043I/L

Genes: 5290

Variants: G1049R H1047R M1043I/L

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the H1047R variant alters the binding interactions and structural dynamics of the protein in response to pY binding, indicating a change in molecular function.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the H1047R and G1049R variants alter the molecular interactions and conformations within the kinase domain, indicating a change in biochemical function related to the protein's activity. Oncogenic: The evidence suggests that the H1047R and G1049R variants contribute to activation through disruption of the inhibitory conformation, which is indicative of their role in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional

Justification: Functional: The passage discusses changes observed for the H1047R variant in the context of HDX-MS experiments, indicating that it alters molecular or biochemical function, specifically in terms of perturbations in conformation.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how C-terminal mutations, including M1043L, H1047R, G1049R, and N1068fs, affect the inhibitory interaction with the C-terminus, indicating an alteration in molecular function. Oncogenic: The mention of "oncogenic mutation" in relation to M1043L, H1047R, and G1049R suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants H1047R, G1049R, M1043L, and N1068fs alter membrane binding and ATPase activity, indicating changes in molecular function. Oncogenic: The variants are described in the context of their effects on membrane binding and ATPase activity, which suggests a role in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the intrinsic ATPase activity of the p110alpha mutants, indicating that the variants G1049R, H1047R, and M1043L alter molecular function by exhibiting significantly increased ATPase activity compared to wild type. Oncogenic: The context of the passage implies that the variants are somatic mutations in a cancer-related gene, contributing to tumor development or progression through their altered biochemical activity.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses frequent oncogenic mutants and their role in tumor samples, indicating that these variants contribute to tumor development or progression. Functional: The analysis of the mutants and their binding to full-length p85alpha suggests that these variants alter molecular or biochemical function, specifically in the context of their interaction with regulatory complexes.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:H1047R/L 5290:M1043L 5290:M1043L/I 5290:N1044K 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the H1047R mutation in the context of its role in activating the kinase domain and increasing membrane binding, indicating its contribution to tumor development or progression. Functional: The passage describes how the H1047R mutation alters the molecular interactions and structural organization of the kinase domain, affecting its binding properties and functionality.

Gene→Variant (gene-first): 5290:H1047R 5290:His1047 5290:Met1043

Genes: 5290

Variants: H1047R His1047 Met1043

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the E726K variant in the context of oncogenic mutations and its association with conformational changes that contribute to tumor development, indicating its role in cancer progression. Functional: The passage describes how the E726K variant leads to conformational changes affecting the interaction between the ABD and p85 with the catalytic core, suggesting an alteration in molecular function.

Gene→Variant (gene-first): 5290:E726K

Genes: 5290

Variants: E726K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the N345K variant affects the molecular interactions and binding of the p110alpha/p85alpha complex to membranes, indicating an alteration in biochemical function.

Gene→Variant (gene-first): 5290:N345K

Genes: 5290

Variants: N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses oncogenic mutants (N345K, G106V, and G118D) and their expected role in promoting ABD/iSH2 disengagement, indicating their contribution to tumor development or progression. Functional: The data suggests that the variants alter the dynamics of the ABD-p85 complex and its interaction with the p110alpha catalytic core, indicating a change in molecular function related to binding and mobility.

Gene→Variant (gene-first): 5290:G106V 5290:G118D 5290:N345K

Genes: 5290

Variants: G106V G118D N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional

Justification: Functional: The passage discusses the D915N mutation in the context of its effect on protein conformation and membrane binding, indicating that it alters molecular function as assessed by HDX-MS experiments.

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

[Paragraph-level] PMCID: PMC9837058 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how mutations in PIK3CA, including G1049R, H1047R, and M1043I/L, contribute to the activation of the PI3K pathway, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the conformation and binding properties of the p110alpha subunit, indicating that these variants affect molecular function related to PI3K activation.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043I/L

Genes: 5290

Variants: G1049R H1047R M1043I/L

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the H1047R variant alters the binding interactions and structural dynamics of the protein in response to pY binding, indicating a change in molecular function.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the H1047R and G1049R variants alter the molecular interactions and conformations within the kinase domain, indicating a change in biochemical function related to the protein's activity. Oncogenic: The evidence suggests that the H1047R and G1049R variants contribute to activation through disruption of the inhibitory conformation, which is indicative of their role in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional

Justification: Functional: The passage discusses changes observed for the H1047R variant in the context of HDX-MS experiments, indicating that it alters molecular or biochemical function, specifically in terms of perturbations in conformation.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how C-terminal mutations, including M1043L, H1047R, G1049R, and N1068fs, affect the inhibitory interaction with the C-terminus, indicating an alteration in molecular function. Oncogenic: The mention of "oncogenic mutation" in relation to M1043L, H1047R, and G1049R suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants H1047R, G1049R, M1043L, and N1068fs alter membrane binding and ATPase activity, indicating changes in molecular function. Oncogenic: The variants are described in the context of their effects on membrane binding and ATPase activity, which suggests a role in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the intrinsic ATPase activity of the p110alpha mutants, indicating that the variants G1049R, H1047R, and M1043L alter molecular function by exhibiting significantly increased ATPase activity compared to wild type. Oncogenic: The context of the passage implies that the variants are somatic mutations in a cancer-related gene, contributing to tumor development or progression through their altered biochemical activity.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses frequent oncogenic mutants and their role in tumor samples, indicating that these variants contribute to tumor development or progression. Functional: The analysis of the mutants and their binding to full-length p85alpha suggests that these variants alter molecular or biochemical function, specifically in the context of their interaction with regulatory complexes.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:H1047R/L 5290:M1043L 5290:M1043L/I 5290:N1044K 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the H1047R mutation in the context of its role in activating the kinase domain and increasing membrane binding, indicating its contribution to tumor development or progression. Functional: The passage describes how the H1047R mutation alters the molecular interactions and structural organization of the kinase domain, affecting its binding properties and functionality.

Gene→Variant (gene-first): 5290:H1047R 5290:His1047 5290:Met1043

Genes: 5290

Variants: H1047R His1047 Met1043

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the E726K variant in the context of oncogenic mutations and its association with conformational changes that contribute to tumor development, indicating its role in cancer progression. Functional: The passage describes how the E726K variant leads to conformational changes affecting the interaction between the ABD and p85 with the catalytic core, suggesting an alteration in molecular function.

Gene→Variant (gene-first): 5290:E726K

Genes: 5290

Variants: E726K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the N345K variant affects the molecular interactions and binding of the p110alpha/p85alpha complex to membranes, indicating an alteration in biochemical function.

Gene→Variant (gene-first): 5290:N345K

Genes: 5290

Variants: N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses oncogenic mutants (N345K, G106V, and G118D) and their expected role in promoting ABD/iSH2 disengagement, indicating their contribution to tumor development or progression. Functional: The data suggests that the variants alter the dynamics of the ABD-p85 complex and its interaction with the p110alpha catalytic core, indicating a change in molecular function related to binding and mobility.

Gene→Variant (gene-first): 5290:G106V 5290:G118D 5290:N345K

Genes: 5290

Variants: G106V G118D N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional

Justification: Functional: The passage discusses the D915N mutation in the context of its effect on protein conformation and membrane binding, indicating that it alters molecular function as assessed by HDX-MS experiments.

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N