[Paper-level Aggregated] PMCID: PMC5873857

Evidence Type(s): Functional

Summary: Mutation: c.159_173del | Summary: The c.159_173del variant alters the molecular function of the MAP2K1 gene, which is implicated in the RAS/MAPK signaling pathway, and is predicted to affect the integrity of helix A, indicating a biochemical impact relevant to the clinical phenotype observed in patients with arteriovenous malformations (AVMs).

Evidence Type: Functional Mutation: E62del | Summary: The deletion of residues 58-62 (E62del) is predicted to affect the integrity of helix A, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: K57 | Summary: K57 is identified as a critical amino acid involved in a hydrogen bond interaction, suggesting its role in the molecular function of the protein.

Evidence Type: Functional Mutation: c.173_187del | Summary: The deletion c.173_187del is predicted to affect the integrity of helix A, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: p.[K57N] | Summary: The missense variant p.[K57N] is associated with critical interactions in the protein structure, suggesting an alteration in molecular function.

Gene→Variant (gene-first): MAP2K1(5604):c.159_173del MAP2K1(5604):E62del NA:K57 MAP2K1(5604):c.173_187del MAP2K1(5604):p.[K57N]

Genes: MAP2K1(5604) NA

Variants: c.159_173del E62del K57 c.173_187del p.[K57N]

[Paper-level Aggregated] PMCID: PMC5873857

Evidence Type(s): Oncogenic

Summary: Mutation: c.159_173del | Summary: The variant c.159_173del is part of a cluster of pathogenic variants identified in MAP2K1, contributing to the development of arteriovenous malformations (AVMs) and indicating its role in tumor progression within the RAS/MAPK signaling pathway.

Evidence Type: Oncogenic Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development by leading to disordered vessel formation and impaired blood flow in zebrafish models, recapitulating clinical features of vascular malformations.

Gene→Variant (gene-first): MAP2K1(5604):c.159_173del BRAF(673):BRAFV600E

Genes: MAP2K1(5604) BRAF(673)

Variants: c.159_173del BRAFV600E

[Paper-level Aggregated] PMCID: PMC5873857

Evidence Type(s): Predictive

Summary: Mutation: BRAFV600E | Summary: The BRAFV600E mutation correlates with response to vemurafenib treatment, an approved BRAF inhibitor, as zebrafish with this mutation exhibited improved blood flow following therapy.

Gene→Variant (gene-first): BRAF(673):BRAFV600E

Genes: BRAF(673)

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Predictive

Summary: Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development by leading to disordered vessel formation and impaired blood flow in zebrafish models, recapitulating clinical features of vascular malformations. Evidence Type: Predictive | Mutation: BRAFV600E | Summary: The BRAFV600E mutation correlates with response to vemurafenib treatment, an approved BRAF inhibitor, as zebrafish with this mutation exhibited improved blood flow following therapy.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E62del | Summary: The deletion of residues 58-62 (E62del) is predicted to affect the integrity of helix A, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: K57 | Summary: K57 is identified as a critical amino acid involved in a hydrogen bond interaction, suggesting its role in the molecular function of the protein. Evidence Type: Functional | Mutation: c.159_173del | Summary: The novel deletion c.159_173del is predicted to affect the integrity of helix A, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: c.173_187del | Summary: The deletion c.173_187del is predicted to affect the integrity of helix A, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: p.[K57N] | Summary: The missense variant p.[K57N] is associated with critical interactions in the protein structure, suggesting an alteration in molecular function.

Gene→Variant (gene-first): 5604:E62del NA:K57 5604:c.159_173del 5604:c.173_187del 5604:p.[K57N]

Genes: 5604 NA

Variants: E62del K57 c.159_173del c.173_187del p.[K57N]

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: c.159_173del | Summary: The variant c.159_173del is part of a cluster of pathogenic variants identified in MAP2K1, contributing to the development of arteriovenous malformations (AVMs) and indicating its role in tumor progression within the RAS/MAPK signaling pathway. Evidence Type: Functional | Mutation: c.159_173del | Summary: The c.159_173del variant alters the molecular function of the MAP2K1 gene, which is implicated in the RAS/MAPK signaling pathway, suggesting a biochemical impact relevant to the clinical phenotype observed in patients with AVMs.

Gene→Variant (gene-first): 5604:c.159_173del

Genes: 5604

Variants: c.159_173del

[Paper-level Aggregated] PMCID: PMC5873857

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The BRAFV600E variant is described as leading to disordered vessel formation and recapitulating clinical features of vascular malformations (VMs), indicating its role in tumorigenesis. Functional: The structural modeling of variants, including deletions and missense mutations, suggests that they affect the integrity of the protein structure and function of MAP2K1, indicating a functional impact on the protein's activity. Predictive: The study demonstrates that treatment with vemurafenib, a BRAF inhibitor, improved blood flow in zebrafish models expressing BRAFV600E, suggesting predictive value for therapeutic response based on the presence of this variant.

Gene→Variant (gene-first): BRAF(673):BRAFV600E MAP2K1(5604):E62del NA:K57 MAP2K1(5604):c.159_173del MAP2K1(5604):c.173_187del MAP2K1(5604):p.[K57N]

Genes: BRAF(673) MAP2K1(5604) NA

Variants: BRAFV600E E62del K57 c.159_173del c.173_187del p.[K57N]

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage describes how the BRAFV600E variant contributes to disordered vessel formation and recapitulates clinical features of vascular malformations, indicating its role in tumor development or progression. Predictive: The passage discusses the response of zebrafish with BRAFV600E to vemurafenib, an approved BRAF inhibitor, showing that the variant correlates with improved blood flow following targeted therapy.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants affect the 3D protein structure and stability of helix A in the MAP2K1 gene, indicating that they alter molecular function. Oncogenic: The variants are described as contributing to the destabilization of the conformation of the inactive state of the protein, which suggests a role in tumor development or progression.

Gene→Variant (gene-first): 5604:E62del NA:K57 5604:c.159_173del 5604:c.173_187del 5604:p.[K57N]

Genes: 5604 NA

Variants: E62del K57 c.159_173del c.173_187del p.[K57N]

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of pathogenic variants in patients with vascular malformations (VMs), indicating that these variants are used to classify or define the clinical phenotype associated with the disease. Oncogenic: The identified variant c.159_173del is described as contributing to the allelic spectrum of variants in the RAS/MAPK pathway, which is known to be involved in tumor development and progression, thus supporting its oncogenic potential.

Gene→Variant (gene-first): 5604:c.159_173del

Genes: 5604

Variants: c.159_173del