[Paper-level Aggregated] PMCID: PMC7612475

Evidence Type(s): Functional

Summary: Mutation: K700E | Summary: The SF3B1 K700E mutation alters molecular function by compromising homologous recombination efficiency, inducing unscheduled R-loop formation, and causing replication fork stalling and degradation. It impacts the resolution of Rad51 foci, decreases sister chromatid exchanges, and affects replication fork restart following a transient replication block, leading to increased basal DNA damage and impaired DNA repair processes.

Evidence Type: Functional Mutation: D210N | Summary: The D210N substitution in RNaseH1 alters its ability to resolve R-loops, leading to their accumulation, which is assessed through fluorescence microscopy.

Gene→Variant (gene-first): SF3B1(23451):K700E RNASEH1(246243):D210N

Genes: SF3B1(23451) RNASEH1(246243)

Variants: K700E D210N

[Paper-level Aggregated] PMCID: PMC7612475

Evidence Type(s): Oncogenic

Summary: Mutation: K700E | Summary: The SF3B1 K700E mutation contributes to tumor development by inducing a BRCA-like cellular phenotype, impairing the repair of DNA double-strand breaks, and compromising replication fork stability. It is associated with defects in homologous recombination, increased DNA damage, and slower growth rates of xenografts compared to wild-type. The mutation also confers synthetic lethality to DNA damaging agents and PARP inhibitors, indicating its role in tumor progression.

Evidence Type: Oncogenic Mutation: D210N | Summary: The D210N mutation contributes to the accumulation of R-loops, leading to increased genome instability, which is associated with tumor development.

Gene→Variant (gene-first): SF3B1(23451):K700E RNASEH1(246243):D210N

Genes: SF3B1(23451) RNASEH1(246243)

Variants: K700E D210N

[Paper-level Aggregated] PMCID: PMC7612475

Evidence Type(s): Predictive

Summary: Mutation: K700E | Summary: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, suggesting a correlation with treatment response. Additionally, the SF3B1K700E mutation is hypothesized to be therapeutically exploitable, as treatment with etoposide or olaparib significantly reduced the volume of tumours with this mutation compared to wild-type tumours.

Gene→Variant (gene-first): SF3B1(23451):K700E

Genes: SF3B1(23451)

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 19

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: K700E | Summary: The SF3B1K700E mutation is hypothesized to be therapeutically exploitable, as treatment with etoposide or olaparib significantly reduced the volume of tumours with this mutation compared to wild-type tumours. Evidence Type: Oncogenic | Mutation: K700E | Summary: The SF3B1K700E mutation contributes to tumor development, as indicated by the slower growth rate of xenografts compared to wild-type, and the presence of increased DNA damage in tumours with this mutation.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K700E | Summary: The SF3B1 K700E mutation is associated with a BRCA-like phenotype, contributing to tumor development by compromising replication fork stability and exhibiting cellular deficits characteristic of BRCA1/2 loss. Evidence Type: Functional | Mutation: K700E | Summary: The K700E mutation alters the molecular function of SF3B1, leading to increased fork degradation and failure to recruit Rad51 to stalled replication forks.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K700E | Summary: The SF3B1K700E mutation alters the efficiency of replication fork restart following a transient replication block, indicating a change in molecular function related to DNA replication dynamics.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: D210N | Summary: The D210N substitution in RNaseH1 alters its ability to resolve R-loops, leading to their accumulation, which is assessed through fluorescence microscopy. Evidence Type: Oncogenic | Mutation: D210N | Summary: The D210N mutation contributes to the accumulation of R-loops, which can lead to increased genome instability, a factor associated with tumor development.

Gene→Variant (gene-first): 246243:D210N

Genes: 246243

Variants: D210N

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K700E | Summary: The SF3B1 K700E mutation alters molecular function by inducing unscheduled R-loops and stalled replication forks, impacting replication fork protection and restart.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K700E | Summary: The SF3B1K700E mutation alters the molecular function of homologous recombination (HR) by affecting the resolution of Rad51 foci and decreasing sister chromatid exchanges, indicating a defect in HR repair processes. Evidence Type: Oncogenic | Mutation: K700E | Summary: The SF3B1K700E mutation contributes to tumor development or progression by impairing the repair of DNA double-strand breaks, which is critical for maintaining genomic stability.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K700E | Summary: The SF3B1K700E mutation alters the molecular function related to DNA repair, as evidenced by impaired homologous recombination (HR) and increased basal DNA damage in cells expressing this mutation. Evidence Type: Oncogenic | Mutation: K700E | Summary: The SF3B1K700E mutation contributes to tumor development or progression, as indicated by its association with defects in double-strand break (DSB) repair and its presence in cancer-derived cell lines.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: K700E | Summary: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, suggesting a correlation with treatment response. Evidence Type: Functional | Mutation: K700E | Summary: The K700E mutation alters molecular function by compromising homologous recombination efficiency and inducing unscheduled R-loop formation, replication fork stalling, and defective replication fork restart. Evidence Type: Oncogenic | Mutation: K700E | Summary: The K700E mutation contributes to tumor development by inducing a BRCA-like cellular phenotype that confers synthetic lethality to DNA damaging agents and PARP inhibitors.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paper-level Aggregated] PMCID: PMC7612475

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The SF3B1K700E mutation is associated with a BRCA-like cellular phenotype that compromises homologous recombination (HR) and increases sensitivity to DNA damaging agents, indicating its role in cancer development. Functional: The SF3B1K700E mutation affects the ability of cells to resolve recombination intermediates and induces unscheduled R-loops, leading to stalled replication forks and reduced replication fork protection, demonstrating a functional impact on DNA repair mechanisms. Predictive: The presence of the SF3B1K700E mutation predicts increased sensitivity to PARP inhibitors and other chemotherapeutic agents, suggesting its potential as a therapeutic target in cancer treatment.

Gene→Variant (gene-first): RNASEH1(246243):D210N SF3B1(23451):K700E

Genes: RNASEH1(246243) SF3B1(23451)

Variants: D210N K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 19

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the SF3B1K700E mutation can be therapeutically targeted, indicating a correlation with treatment response to etoposide and olaparib, which are specific therapies. Oncogenic: The SF3B1K700E mutation is implicated in tumor development, as the passage describes its role in creating an HR defect and its effects on tumor growth in xenograft models.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the SF3B1 K700E variant contributes to cellular deficits characteristic of BRCA1/2 loss, indicating its role in tumor development or progression. Functional: The variant K700E is shown to alter the recruitment of Rad51 to replication forks and affects replication fork stability, demonstrating a change in molecular function.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E variant affects replication fork dynamics and efficiency of replication fork restart, indicating an alteration in molecular function related to DNA replication. Oncogenic: The context of the study involves assessing the impact of the SF3B1K700E mutation on cellular processes relevant to tumor development, such as replication fork dynamics, which suggests a role in oncogenesis.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The D210N variant is described as being catalytically inactivated, which alters its ability to resolve R-loops, indicating a change in molecular function. Oncogenic: The passage discusses the role of the D210N variant in the context of R-loop accumulation and genome instability, which are associated with tumor development and progression.

Gene→Variant (gene-first): 246243:D210N

Genes: 246243

Variants: D210N

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the K700E mutation alters molecular function by inducing unscheduled R-loops and affecting replication fork dynamics.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E mutation alters the molecular function of homologous recombination (HR) by affecting the formation and resolution of Rad51 foci, indicating a defect in the later stages of HR. Oncogenic: The SF3B1K700E mutation is implicated in tumor development or progression as it affects the ability of cells to resolve recombination intermediates, which is a critical process in maintaining genomic stability in cancer cells.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E variant alters the ability of cells to resolve DNA double-strand breaks (DSBs) and impairs homologous recombination (HR) repair, indicating a change in molecular function related to DNA repair mechanisms. Oncogenic: The SF3B1K700E mutation is described as cancer-associated and is shown to contribute to defects in DNA repair, which is a characteristic of oncogenic variants that promote tumor development or progression.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional

Justification: Predictive: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, indicating a correlation with treatment response. Functional: The K700E mutation alters HR efficiency and induces unscheduled R-loop formation, replication fork stalling, and defective replication fork restart, demonstrating an impact on molecular function.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 19

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the SF3B1K700E mutation can be therapeutically targeted, indicating a correlation with treatment response to etoposide and olaparib, which are specific therapies. Oncogenic: The SF3B1K700E mutation is implicated in tumor development, as the passage describes its role in creating an HR defect and its effects on tumor growth in xenograft models.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the SF3B1 K700E variant contributes to cellular deficits characteristic of BRCA1/2 loss, indicating its role in tumor development or progression. Functional: The variant K700E is shown to alter the recruitment of Rad51 to replication forks and affects replication fork stability, demonstrating a change in molecular function.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E variant affects replication fork dynamics and efficiency of replication fork restart, indicating an alteration in molecular function related to DNA replication. Oncogenic: The context of the study involves assessing the impact of the SF3B1K700E mutation on cellular processes relevant to tumor development, such as replication fork dynamics, which suggests a role in oncogenesis.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The D210N variant is described as being catalytically inactivated, which alters its ability to resolve R-loops, indicating a change in molecular function. Oncogenic: The passage discusses the role of the D210N variant in the context of R-loop accumulation and genome instability, which are associated with tumor development and progression.

Gene→Variant (gene-first): 246243:D210N

Genes: 246243

Variants: D210N

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the K700E mutation alters molecular function by inducing unscheduled R-loops and affecting replication fork dynamics.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E mutation alters the molecular function of homologous recombination (HR) by affecting the formation and resolution of Rad51 foci, indicating a defect in the later stages of HR. Oncogenic: The SF3B1K700E mutation is implicated in tumor development or progression as it affects the ability of cells to resolve recombination intermediates, which is a critical process in maintaining genomic stability in cancer cells.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E variant alters the ability of cells to resolve DNA double-strand breaks (DSBs) and impairs homologous recombination (HR) repair, indicating a change in molecular function related to DNA repair mechanisms. Oncogenic: The SF3B1K700E mutation is described as cancer-associated and is shown to contribute to defects in DNA repair, which is a characteristic of oncogenic variants that promote tumor development or progression.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional

Justification: Predictive: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, indicating a correlation with treatment response. Functional: The K700E mutation alters HR efficiency and induces unscheduled R-loop formation, replication fork stalling, and defective replication fork restart, demonstrating an impact on molecular function.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E