[Paper-level Aggregated] PMCID: PMC4748120

Evidence Type(s): Functional

Summary: Mutation: K-RasG12D | Summary: The K-RasG12D mutation alters the growth response of myeloid progenitors to GM-CSF, exhibits resistance to GAP stimulation, and is associated with increased levels of Ras-GTP, pERK, and pAkt in Ba/F3 cells under serum deprivation, indicating multiple changes in molecular function related to signaling pathways and colony formation.

Evidence Type: Functional Mutation: A66dup | Summary: The A66dup mutation in K-Ras sensitizes myeloid progenitors to GM-CSF, alters molecular function by increasing levels of Ras-GTP in Ba/F3 cells under serum deprivation, reduces intrinsic GTP hydrolysis rates, and impairs PI3 kinase binding, demonstrating its impact on biochemical activity.

Evidence Type: Functional Mutation: Glutamine 61; Q61 | Summary: The Glutamine 61 (Q61) mutation may alter molecular function due to structural changes from switch 2 insertions, affecting protein-protein interactions and the GTP conformation of Ras.

Evidence Type: Functional Mutation: Y64G | Summary: The Y64G mutation in K-Ras, when combined with K-RasG12D, results in significantly reduced binding to FLAG-p110alpha, indicating an alteration in molecular function.

Gene→Variant (gene-first): KRAS(3845):K-RasG12D PIK3R1(5295):A66dup KRAS(3845):Glutamine 61 KRAS(3845):Q61 PIK3CA(5290):Y64G

Genes: KRAS(3845) PIK3R1(5295) PIK3CA(5290)

Variants: K-RasG12D A66dup Glutamine 61 Q61 Y64G

[Paper-level Aggregated] PMCID: PMC4748120

Evidence Type(s): Oncogenic

Summary: Mutation: c.178_198dup | Summary: The c.178_198dup variant is a partial duplication of the switch 2 domain of K-Ras, which is associated with juvenile myelomonocytic leukaemia (JMML) and contributes to tumor development.

Evidence Type: Oncogenic Mutation: c.184_198dup | Summary: The c.184_198dup variant is a tandem duplication found in lung adenocarcinomas and colorectal cancer, indicating its role in tumor progression.

Evidence Type: Oncogenic Mutation: K-RasG12D | Summary: The K-RasG12D mutation contributes to tumor development by promoting cytokine-independent growth in Ba/F3 cells and hematopoietic progenitor cells, and is associated with elevated signaling pathways indicative of oncogenic activity.

Evidence Type: Oncogenic Mutation: A66dup | Summary: The A66dup mutation in K-Ras is associated with tumor development and progression, as it transforms the growth of primary myeloid progenitors and Ba/F3 cells, indicating its oncogenic potential.

Gene→Variant (gene-first): KRAS(3845):c.178_198dup KRAS(3845):c.184_198dup KRAS(3845):K-RasG12D PIK3R1(5295):A66dup

Genes: KRAS(3845) PIK3R1(5295)

Variants: c.178_198dup c.184_198dup K-RasG12D A66dup

[Paper-level Aggregated] PMCID: PMC4748120

Evidence Type(s): Diagnostic

Summary: Mutation: A66dup | Summary: The presence of the A66dup mutation in K-Ras has diagnostic implications, as it is associated with an atypical myeloproliferative neoplasm in the patient described.

Gene→Variant (gene-first): PIK3R1(5295):A66dup

Genes: PIK3R1(5295)

Variants: A66dup

[Paper-level Aggregated] PMCID: PMC4748120

Evidence Type(s): Predictive

Summary: Mutation: K-RasG12D | Summary: The sensitivity of Ba/F3 cells expressing K-RasG12D to MEK inhibition suggests that this mutation correlates with response to specific therapies, indicating predictive value.

Gene→Variant (gene-first): KRAS(3845):K-RasG12D

Genes: KRAS(3845)

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional, Diagnostic

Summary: Evidence Type: Oncogenic | Mutation: A66dup | Summary: The A66dup mutation in K-Ras is associated with tumor development and progression, as it transforms the growth of primary myeloid progenitors and Ba/F3 cells, indicating its oncogenic potential. Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation alters the molecular function of K-Ras by reducing intrinsic GTP hydrolysis rates and impairing PI3 kinase binding, demonstrating its impact on biochemical activity. Evidence Type: Diagnostic | Mutation: A66dup | Summary: The presence of the A66dup mutation in K-Ras has diagnostic implications, as it is associated with an atypical myeloproliferative neoplasm in the patient described.

Gene→Variant (gene-first): 5295:A66dup

Genes: 5295

Variants: A66dup

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Predictive, Oncogenic

Summary: Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation is associated with defective PI3K binding and Akt activation, indicating an alteration in molecular function related to signaling pathways. Evidence Type: Predictive | Mutation: K-RasG12D | Summary: The sensitivity of Ba/F3 cells expressing K-RasG12D to MEK inhibition suggests that this mutation correlates with response to specific therapies, indicating predictive value. Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation contributes to the transformed, cytokine-independent growth of Ba/F3 cells, indicating its role in tumor development.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation in K-Ras shows a markedly reduced interaction with FLAG-p110alpha, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation is associated with a profound reduction in binding to FLAG-p110alpha, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: Y64G | Summary: The Y64G mutation in K-Ras, when combined with K-RasG12D, results in a significantly reduced binding to FLAG-p110alpha, indicating an alteration in molecular function.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D 5290:Y64G

Genes: 5295 3845 5290

Variants: A66dup K-RasG12D Y64G

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation alters molecular function, as indicated by the increased levels of pERK and pAkt in response to its expression in Ba/F3 cells. Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation contributes to tumor development or progression, as it is associated with elevated signaling pathways indicative of oncogenic activity.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D variant contributes to tumor development by transforming IL-3-dependent Ba/F3 cells to cytokine-independent growth. Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D variant alters molecular function by increasing levels of Ras-GTP in Ba/F3 cells under serum deprivation. Evidence Type: Oncogenic | Mutation: A66dup | Summary: The A66dup variant contributes to tumor development by transforming IL-3-dependent Ba/F3 cells to cytokine-independent growth. Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup variant alters molecular function by increasing levels of Ras-GTP in Ba/F3 cells under serum deprivation.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation alters the biochemical properties of K-Ras, leading to impaired intrinsic GTPase activity and increased accumulation in the active GTP conformation. Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation exhibits resistance to GAP stimulation and altered GTPase activity, indicating a change in molecular function.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Glutamine 61; Q61 | Summary: The passage discusses potential effects on the molecular function of Glutamine 61 (Q61) due to structural changes from switch 2 insertions, indicating alterations in protein-protein interactions and the GTP conformation of Ras. Evidence Type: Oncogenic | Mutation: Glutamine 61; Q61 | Summary: The analysis suggests that alterations involving Q61 may contribute to tumor development or progression by favoring the GTP conformation of Ras, which is associated with oncogenic activity.

Gene→Variant (gene-first): 3845:Glutamine 61 3845:Q61

Genes: 3845

Variants: Glutamine 61 Q61

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation induces cytokine-independent colony formation and contributes to tumor development by promoting hypersensitive growth patterns in hematopoietic progenitor cells. Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation alters the growth response of myeloid progenitors to GM-CSF, indicating a change in molecular function related to colony formation. Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation in K-Ras insertion variants sensitizes myeloid progenitors to GM-CSF, suggesting an alteration in biochemical function related to growth response.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: c.178_198dup | Summary: The c.178_198dup variant is a partial duplication of the switch 2 domain of K-Ras, which is associated with juvenile myelomonocytic leukaemia (JMML) and contributes to tumor development. Evidence Type: Oncogenic | Mutation: c.184_198dup | Summary: The c.184_198dup variant is a tandem duplication found in lung adenocarcinomas and colorectal cancer, indicating its role in tumor progression.

Gene→Variant (gene-first): 3845:c.178_198dup 3845:c.184_198dup

Genes: 3845

Variants: c.178_198dup c.184_198dup

[Paper-level Aggregated] PMCID: PMC4748120

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The text describes a partial duplication of the switch 2 domain of K-Ras, which is associated with transforming growth in myeloid progenitors and Ba/F3 cells, indicating its role as an oncogenic mutation. Functional: The study demonstrates that K-Ras proteins with switch 2 insertions exhibit reduced intrinsic GTP hydrolysis rates and accumulate in the GTP-bound conformation, indicating altered functional properties of these mutant proteins. Predictive: The findings suggest that K-Ras mutations, including the switch 2 duplications, may influence the sensitivity of transformed cells to MEK and PI3K inhibitors, indicating potential predictive value for therapeutic responses.

Gene→Variant (gene-first): PIK3R1(5295):A66dup KRAS(3845):K-RasG12D PIK3CA(5290):Y64G KRAS(3845):Glutamine 61 KRAS(3845):Q61 KRAS(3845):c.178_198dup KRAS(3845):c.184_198dup

Genes: PIK3R1(5295) KRAS(3845) PIK3CA(5290)

Variants: A66dup K-RasG12D Y64G Glutamine 61 Q61 c.178_198dup c.184_198dup

[Paragraph-level] PMCID: PMC4748120 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive, Diagnostic

Justification: Oncogenic: The passage describes how the A66dup variant contributes to tumor development by transforming the growth of primary myeloid progenitors and Ba/F3 cells, indicating its role in oncogenesis. Predictive: The passage mentions that K-Ras proteins with the A66dup variant are hypersensitive to MEK inhibition, suggesting a correlation with response to a specific therapy. Diagnostic: The discovery of the A66dup variant in a child with an atypical myeloproliferative neoplasm suggests its potential use in defining or classifying this disease.

Gene→Variant (gene-first): 5295:A66dup

Genes: 5295

Variants: A66dup

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of cells expressing K-RasG12D to specific therapies, indicating a correlation between the variant and response to treatment with MEK and PI3K inhibitors. Oncogenic: The mention of K-RasG12D in the context of transformed Ba/F3 cells suggests that this somatic variant contributes to tumor development or progression, as it is involved in cytokine-independent growth.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the ability of mutant K-Ras proteins to bind to effectors in vitro, indicating that the variants alter molecular interactions, specifically the binding to FLAG-p110alpha. Oncogenic: The mention of K-RasG12D and the other mutant variants in the context of their binding interactions suggests that these somatic variants contribute to tumor development or progression through their altered functional properties.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D 5290:Y64G

Genes: 5295 3845 5290

Variants: A66dup K-RasG12D Y64G

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K-RasG12D variant alters the levels of pERK and pAkt, indicating a change in molecular function related to signaling pathways. Oncogenic: The K-RasG12D variant is implicated in modulating effector pathway activation, which suggests its role in tumor development or progression.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the K-RasG12D variant and tandem duplication mutants transform Ba/F3 cells to cytokine-independent growth, indicating their role in tumor development or progression. Functional: The passage mentions that Ba/F3 cells expressing K-RasG12D and the tandem duplication mutants had elevated levels of Ras-GTP, suggesting that these variants alter molecular function related to Ras signaling.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants K-RasG60_A66dup and K-RasE62_A66dup alter the biochemical properties of K-Ras, specifically their GTPase activity and response to GAP stimulation, indicating a change in molecular function. Oncogenic: The variants are described in the context of their role in accumulating in the active GTP conformation and exhibiting impaired GTPase activity, which suggests their contribution to tumor development or progression.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant Glutamine 61 (Q61) may alter protein-protein interactions and the structural dynamics of Ras, indicating a change in molecular function due to the predicted effects of switch 2 insertions. Oncogenic: The analysis suggests that the alterations in the Ras protein structure, particularly involving Q61, may contribute to the GTP conformation of Ras, which is associated with tumor development and progression.

Gene→Variant (gene-first): 3845:Glutamine 61 3845:Q61

Genes: 3845

Variants: Glutamine 61 Q61

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the K-RasG12D variant induces cytokine-independent colony formation and contributes to abnormal growth patterns in hematopoietic progenitor cells, indicating its role in tumor development. Functional: The variant K-RasG12D alters the growth response of progenitor cells to GM-CSF, demonstrating a change in molecular function related to colony formation.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes a partial duplication of the K-Ras gene that is associated with juvenile myelomonocytic leukaemia (JMML), indicating that the variant contributes to tumor development or progression. Functional: The immunoblot analysis shows that the variant alters the molecular function of K-Ras, as evidenced by the detection of a band with reduced electrophoretic mobility compared to normal Ras protein, indicating a change in protein behavior.

Gene→Variant (gene-first): 3845:c.178_198dup 3845:c.184_198dup

Genes: 3845

Variants: c.178_198dup c.184_198dup

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of cells expressing K-RasG12D to specific therapies, indicating a correlation between the variant and response to treatment with MEK and PI3K inhibitors. Oncogenic: The mention of K-RasG12D in the context of transformed Ba/F3 cells suggests that this somatic variant contributes to tumor development or progression, as it is involved in cytokine-independent growth.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the ability of mutant K-Ras proteins to bind to effectors in vitro, indicating that the variants alter molecular interactions, specifically the binding to FLAG-p110alpha. Oncogenic: The mention of K-RasG12D and the other mutant variants in the context of their binding interactions suggests that these somatic variants contribute to tumor development or progression through their altered functional properties.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D 5290:Y64G

Genes: 5295 3845 5290

Variants: A66dup K-RasG12D Y64G

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K-RasG12D variant alters the levels of pERK and pAkt, indicating a change in molecular function related to signaling pathways. Oncogenic: The K-RasG12D variant is implicated in modulating effector pathway activation, which suggests its role in tumor development or progression.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the K-RasG12D variant and tandem duplication mutants transform Ba/F3 cells to cytokine-independent growth, indicating their role in tumor development or progression. Functional: The passage mentions that Ba/F3 cells expressing K-RasG12D and the tandem duplication mutants had elevated levels of Ras-GTP, suggesting that these variants alter molecular function related to Ras signaling.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants K-RasG60_A66dup and K-RasE62_A66dup alter the biochemical properties of K-Ras, specifically their GTPase activity and response to GAP stimulation, indicating a change in molecular function. Oncogenic: The variants are described in the context of their role in accumulating in the active GTP conformation and exhibiting impaired GTPase activity, which suggests their contribution to tumor development or progression.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant Glutamine 61 (Q61) may alter protein-protein interactions and the structural dynamics of Ras, indicating a change in molecular function due to the predicted effects of switch 2 insertions. Oncogenic: The analysis suggests that the alterations in the Ras protein structure, particularly involving Q61, may contribute to the GTP conformation of Ras, which is associated with tumor development and progression.

Gene→Variant (gene-first): 3845:Glutamine 61 3845:Q61

Genes: 3845

Variants: Glutamine 61 Q61

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the K-RasG12D variant induces cytokine-independent colony formation and contributes to abnormal growth patterns in hematopoietic progenitor cells, indicating its role in tumor development. Functional: The variant K-RasG12D alters the growth response of progenitor cells to GM-CSF, demonstrating a change in molecular function related to colony formation.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes a partial duplication of the K-Ras gene that is associated with juvenile myelomonocytic leukaemia (JMML), indicating that the variant contributes to tumor development or progression. Functional: The immunoblot analysis shows that the variant alters the molecular function of K-Ras, as evidenced by the detection of a band with reduced electrophoretic mobility compared to normal Ras protein, indicating a change in protein behavior.

Gene→Variant (gene-first): 3845:c.178_198dup 3845:c.184_198dup

Genes: 3845

Variants: c.178_198dup c.184_198dup