Proposition Profiles

Proposition Profiles are defined as concrete subclasses of the core Proposition class - each tailored to represent a specific type of possible fact that may be true in a domain of discourse. For example, the VariantPathogenicityProposition profile defines a model for describing causal relationships between genetic variants and specific diseases.

Such Propositions are used within the context of the generic Statement class from the core model - whether that Statement stands on its own or serves as an Evidence Line - to provide domain specific semantics for the assessments that the core class provides (e.g. in the example here). This avoids the need to define Statement or Evidence Line profiles for many use cases. (The VA-Spec only defines Statement or Evidence Line profiles to support strict alignment with terminological conventions of a particular community guideline, e.g. the ACMG 2015 Variant Pathogenicity Statement profile).

Below are the VA Standard Proposition Profiles currently defined as part of the VA-Spec, and available for adoption or extension by implementations.

Variant Pathogenicity Proposition

Trial Use

May change in future releases. See Maturity Model.

Computational Definition

A proposition describing the role of a variant in causing a heritable condition.

Information Model

Some VariantPathogenicityProposition attributes are inherited from Genetic Context Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	Must be “VariantPathogenicityProposition”
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		MolecularVariation | CategoricalVariant | iriReference	1..1	A variant that is the subject of the Proposition.
predicate		string	1..1	The relationship the Proposition describes between the subject variant and object condition. MUST be “isCausalFor”.
object		Condition | Condition Set | iriReference	1..1	The Condition or Condition Set for which the variant impact is stated.
geneContextQualifier		Mappable Concept | iriReference	0..1	Reports a gene impacted by the variant, which may contribute to the association described in the Proposition.
alleleOriginQualifier		Mappable Concept | iriReference	0..1	Reports whether the Proposition should be interpreted in the context of a heritable “germline” variant, an acquired “somatic” variant in a tumor, or a post-zygotic “mosaic” variant. While these are the most commonly reported allele origins, other more nuanced concepts can be captured (e.g. “maternal” vs “paternal” allele origin). In practice, populating this field may be complicated by the fact that some sources report allele origin based on the type of tissue that was sequenced to identify the variant, and others use it more generally to specify a category of variant for which the proposition holds. The stated intent of this attribute is the latter. However, if an implementer is not sure about which is reported in their data, it may be safer to create an Extension to hold this information, where they can explicitly acknowledge this ambiguity.
penetranceQualifier		Mappable Concept | iriReference	0..1	Reports the penetrance of the pathogenic effect - i.e. the extent to which the variant impact is expressed by individuals carrying it as a measure of the proportion of carriers exhibiting the condition.
modeOfInheritanceQualifier		Mappable Concept | iriReference	0..1	Reports a pattern of inheritance expected for the pathogenic effect of the variant. Consider using terms or codes from community terminologies here - e.g. terms from the ‘Mode of inheritance’ branch of the Human Phenotype Ontology such as HP:0000006 (autosomal dominant inheritance).

Inherits: Genetic Context Variant Proposition

Used in: Variant Pathogenicity Evidence Line (ACMG 2015), Variant Pathogenicity Statement (ACMG 2015)

Artifacts

• Pathogenicity Proposition Source Yaml

• Pathogenicity Proposition Json Schema

Pathogenicity Proposition Semantics

• The subject, predicate, object attributes defined in this profile can be used to create structured representations of basic propositions such as “NM_005343.4:c.173C>T is causal for Costello Syndrome”.

• Optional qualifier attributes are able to support details like a germline allele origin and HRAS gene context for the variant, and low penetrance and dominant mode of inheritance for the condition.

• These specific attributes were defined to support the needs of early VA-Spec implementations, but may be refined or expanded as additional use cases emerge.

Variant Oncogenicity Proposition

Trial Use

May change in future releases. See Maturity Model.

Computational Definition

A proposition describing the role of a variant in causing a tumor type.

Information Model

Some VariantOncogenicityProposition attributes are inherited from Genetic Context Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “VariantOncogenicityProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		MolecularVariation | CategoricalVariant | iriReference	1..1	A variant that is the subject of the Proposition.
predicate		string	1..1	The relationship the Proposition describes between the subject variant and object tumor type. MUST be “isOncogenicFor”.
object		Condition | Condition Set | iriReference	1..1	The tumor type for which the variant impact is evaluated.
geneContextQualifier		Mappable Concept | iriReference	0..1	Reports a gene impacted by the variant, which may contribute to the association described in the Proposition.
alleleOriginQualifier		Mappable Concept | iriReference	0..1	Reports whether the Proposition should be interpreted in the context of a heritable “germline” variant, an acquired “somatic” variant in a tumor, or a post-zygotic “mosaic” variant. While these are the most commonly reported allele origins, other more nuanced concepts can be captured (e.g. “maternal” vs “paternal” allele origin). In practice, populating this field may be complicated by the fact that some sources report allele origin based on the type of tissue that was sequenced to identify the variant, and others use it more generally to specify a category of variant for which the proposition holds. The stated intent of this attribute is the latter. However, if an implementer is not sure about which is reported in their data, it may be safer to create an Extension to hold this information, where they can explicitly acknowledge this ambiguity.

Inherits: Genetic Context Variant Proposition

Used in: Variant Oncogenicity Evidence Line (CCV 2022), Variant Oncogenicity Statement (CCV 2022)

Artifacts

• Oncogenicity Proposition Source Yaml

• Oncogenicity Proposition Json Schema

Oncogenicity Proposition Semantics

• The subject, predicate, object attributes defined in this profile can be used to create structured representations of basic propositions such as “NP_000305.3:p.Arg11Thr is causal for Breast Carcinoma”.

• Optional qualifier attributes are able to support details like a somatic allele origin and EGFR gene context for the variant.

• These specific attributes were defined to support the needs of early VA-Spec implementations, but may be refined or expanded as additional use cases emerge.

Variant Clinical Significance Proposition

Draft

May change significantly in future releases. See Maturity Model.

Computational Definition

A Proposition describing the clinical significance of a variant with respect to a condition.

Information Model

Some VariantClinicalSignificanceProposition attributes are inherited from Genetic Context Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “VariantClinicalSignificanceProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		MolecularVariation | CategoricalVariant | iriReference	1..1	A variant that is the subject of the Proposition.
predicate		string	1..1	The predicate associating the subject variant to clinical significance for the object Condition. MUST be “hasClinicalSignificanceFor”.
object		Condition | Condition Set | iriReference	1..1	The condition that is evaluated.
geneContextQualifier		Mappable Concept | iriReference	0..1	Reports a gene impacted by the variant, which may contribute to the association described in the Proposition.
alleleOriginQualifier		Mappable Concept | iriReference	0..1	Reports whether the Proposition should be interpreted in the context of a heritable “germline” variant, an acquired “somatic” variant in a tumor, or a post-zygotic “mosaic” variant. While these are the most commonly reported allele origins, other more nuanced concepts can be captured (e.g. “maternal” vs “paternal” allele origin). In practice, populating this field may be complicated by the fact that some sources report allele origin based on the type of tissue that was sequenced to identify the variant, and others use it more generally to specify a category of variant for which the proposition holds. The stated intent of this attribute is the latter. However, if an implementer is not sure about which is reported in their data, it may be safer to create an Extension to hold this information, where they can explicitly acknowledge this ambiguity.

Inherits: Genetic Context Variant Proposition

Used in: Variant Clinical Significance Statement (AAC 2017)

Artifacts

• Clinical Significance Proposition Source Yaml

• Clinical Significance Proposition Json Schema

Variant Therapeutic Response Proposition

Trial Use

May change in future releases. See Maturity Model.

Computational Definition

A Proposition about the role of a variant in modulating the response of a neoplasm to drug administration or other therapeutic procedures.

Information Model

Some VariantTherapeuticResponseProposition attributes are inherited from Genetic Context Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “VariantTherapeuticResponseProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		MolecularVariation | CategoricalVariant | iriReference	1..1	A variant that is the subject of the Proposition.
predicate		string	1..1	The relationship the Proposition describes between the subject variant and object therapeutic. MUST be one of “predictsSensitivityTo” or “predictsResistanceTo”.
object		Therapy | Therapy Group | iriReference	1..1	A drug administration or other therapeutic procedure that the neoplasm is intended to respond to.
geneContextQualifier		Mappable Concept | iriReference	0..1	Reports a gene impacted by the variant, which may contribute to the association described in the Proposition.
alleleOriginQualifier		Mappable Concept | iriReference	0..1	Reports whether the Proposition should be interpreted in the context of a heritable “germline” variant, an acquired “somatic” variant in a tumor, or a post-zygotic “mosaic” variant. While these are the most commonly reported allele origins, other more nuanced concepts can be captured (e.g. “maternal” vs “paternal” allele origin). In practice, populating this field may be complicated by the fact that some sources report allele origin based on the type of tissue that was sequenced to identify the variant, and others use it more generally to specify a category of variant for which the proposition holds. The stated intent of this attribute is the latter. However, if an implementer is not sure about which is reported in their data, it may be safer to create an Extension to hold this information, where they can explicitly acknowledge this ambiguity.
conditionQualifier		Condition | Condition Set | iriReference	1..1	Reports the disease context in which the variant’s association with therapeutic sensitivity or resistance is evaluated. Note that this is a required qualifier in therapeutic response propositions.

Inherits: Genetic Context Variant Proposition

Used in: Variant Amp/Asco/Cap Evidence Line (AAC 2017), Variant Therapeutic Evidence Line (AAC 2017)

Artifacts

• Therapeutic Response Proposition Source Yaml

• Therapeutic Response Proposition Json Schema

Therapeutic Response Proposition Semantics

• The subject, predicate, object attributes defined in this profile can be used to create structured representations of basic propositions such as “EGFR L858R predicts sensitivity to Afatinib”.

• Here, a required conditionQualifier captures the disease context in which the reported association holds (e.g. Lung Adenocarcinoma).

• Other optional qualifiers are able to support details like a somatic allele origin and EGFR gene context for the variant.

• These specific attributes were defined to support the needs of early VA-Spec implementations, but may be refined or expanded as additional use cases emerge.

Variant Diagnostic Proposition

Trial Use

May change in future releases. See Maturity Model.

Computational Definition

A Proposition about whether a variant is associated with a disease (a diagnostic inclusion criterion), or absence of a disease (diagnostic exclusion criterion).

Information Model

Some VariantDiagnosticProposition attributes are inherited from Genetic Context Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “VariantDiagnosticProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		MolecularVariation | CategoricalVariant | iriReference	1..1	A variant that is the subject of the Proposition.
predicate		string	1..1	The relationship the Proposition describes between the subject variant and object Condition. MUST be one of “isDiagnosticInclusionCriterionFor” or “isDiagnosticExclusionCriterionFor”.
object		Condition | Condition Set | iriReference	1..1	The disease that is evaluated for diagnosis.
geneContextQualifier		Mappable Concept | iriReference	0..1	Reports a gene impacted by the variant, which may contribute to the association described in the Proposition.
alleleOriginQualifier		Mappable Concept | iriReference	0..1	Reports whether the Proposition should be interpreted in the context of a heritable “germline” variant, an acquired “somatic” variant in a tumor, or a post-zygotic “mosaic” variant. While these are the most commonly reported allele origins, other more nuanced concepts can be captured (e.g. “maternal” vs “paternal” allele origin). In practice, populating this field may be complicated by the fact that some sources report allele origin based on the type of tissue that was sequenced to identify the variant, and others use it more generally to specify a category of variant for which the proposition holds. The stated intent of this attribute is the latter. However, if an implementer is not sure about which is reported in their data, it may be safer to create an Extension to hold this information, where they can explicitly acknowledge this ambiguity.

Inherits: Genetic Context Variant Proposition

Used in: Variant Amp/Asco/Cap Evidence Line (AAC 2017), Variant Diagnostic Evidence Line (AAC 2017)

Artifacts

• Diagnostic Proposition Source Yaml

• Diagnostic Proposition Json Schema

Diagnostic Proposition Semantics

• The subject, predicate, object attributes defined in this profile can be used to create structured representations of basic propositions such as “EGFR R11T is a diagnostic inclusion criterion for Breast Cancer”.

• Optional qualifier attributes are able to support details like a somatic allele origin and EGFR gene context for the variant.

• These specific attributes were defined to support the needs of early VA-Spec implementations, but may be refined or expanded as additional use cases emerge.

Variant Prognostic Proposition

Trial Use

May change in future releases. See Maturity Model.

Computational Definition

A Proposition about whether a variant is associated with an improved or worse outcome for a disease.

Information Model

Some VariantPrognosticProposition attributes are inherited from Genetic Context Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “VariantPrognosticProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		MolecularVariation | CategoricalVariant | iriReference	1..1	A variant that is the subject of the Proposition.
predicate		string	1..1	The relationship the Proposition describes between the subject variant and object Condition. MUST be one of “associatedWithBetterOutcomeFor” or “associatedWithWorseOutcomeFor”.
object		Condition | Condition Set | iriReference	1..1	The disease that is evaluated for outcome.
geneContextQualifier		Mappable Concept | iriReference	0..1	Reports a gene impacted by the variant, which may contribute to the association described in the Proposition.
alleleOriginQualifier		Mappable Concept | iriReference	0..1	Reports whether the Proposition should be interpreted in the context of a heritable “germline” variant, an acquired “somatic” variant in a tumor, or a post-zygotic “mosaic” variant. While these are the most commonly reported allele origins, other more nuanced concepts can be captured (e.g. “maternal” vs “paternal” allele origin). In practice, populating this field may be complicated by the fact that some sources report allele origin based on the type of tissue that was sequenced to identify the variant, and others use it more generally to specify a category of variant for which the proposition holds. The stated intent of this attribute is the latter. However, if an implementer is not sure about which is reported in their data, it may be safer to create an Extension to hold this information, where they can explicitly acknowledge this ambiguity.

Inherits: Genetic Context Variant Proposition

Used in: Variant Amp/Asco/Cap Evidence Line (AAC 2017), Variant Prognostic Evidence Line (AAC 2017)

Artifacts

• Prognostic Proposition Source Yaml

• Prognostic Proposition Json Schema

Prognostic Proposition Semantics

• The subject, predicate, object attributes defined in this profile can be used to create structured representations of basic propositions such as “EGFR R11T associated with better outcomes for Breast Cancer”.

• Optional qualifier attributes are able to support details like a somatic allele origin and EGFR gene context for the variant.

• These specific attributes were defined to support the needs of early VA-Spec implementations, but may be refined or expanded as additional use cases emerge.

Experimental Variant Functional Impact Proposition

Trial Use

May change in future releases. See Maturity Model.

Computational Definition

A Proposition describing the impact of a variant on the function sequence feature (typically a gene or gene product).

Information Model

Some ExperimentalVariantFunctionalImpactProposition attributes are inherited from Subject Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “ExperimentalVariantFunctionalImpactProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		MolecularVariation | CategoricalVariant | iriReference	1..1	A variant that is the subject of the Proposition.
predicate		string	1..1	The relationship the Proposition describes between the subject variant and object sequence feature whose function it may alter. MUST be “impactsFunctionOf”.
object		iriReference | Mappable Concept	1..1	The sequence feature (typically a gene or gene product) on whose function the impact of the subject variant is reported.
experimentalContextQualifier		iriReference | Document | object	0..1	An assay in which the reported variant functional impact was determined - providing a specific experimental context in which this effect is asserted to hold.

Inherits: Subject Variant Proposition

Artifacts

• Experimental Variant Functional Impact Proposition Source Yaml

• Experimental Variant Functional Impact Proposition Json Schema

Experimental Variant Functional Impact Proposition Semantics

• The subject, predicate, object attributes defined in this profile can be used to create structured representations of basic propositions such as “NP_000305.3:p.Arg11Thr impacts the function of the human PTEN gene”.

• Here, an optional experimentalContextQualifier attribute can reference an assay or analysis that supported the reported impact, which can further inform interpretation of the proposed knowledge.

• These specific attributes were defined to support the needs of an early MAVE-DB implementation of the VA-Spec, and will likely be refined and/or expanded as additional use cases emerge.

Gene Disease Validity Proposition

Draft

May change significantly in future releases. See Maturity Model.

Computational Definition

A proposition that variants affecting a particular Gene are valid for evaluation as causal for some Condition using appropriate variant classification criteria, given a specific mode of inheritance.

Information Model

Some GeneDiseaseValidityProposition attributes are inherited from Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “GeneDiseaseValidityProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		Mappable Concept | iriReference	1..1	The Entity or concept about which the Proposition is made.
predicate		string	1..1	MUST be “variantsInGeneCausalFor”.
object		Mappable Concept | iriReference	1..1	An Entity or concept that is related to the subject of a Proposition via its predicate.
modeOfInheritanceQualifier		Mappable Concept | iriReference	0..1

Inherits: Proposition

Variant Molecular Consequence Proposition

Draft

May change significantly in future releases. See Maturity Model.

Computational Definition

A Proposition describing a predicted molecular consequence of a variant on transcript and protein molecules - typically reporting the type of sequence feature affected (e.g. ‘intron variant’, ‘splice-site variant’), or an impact on the processing of the molecule along the path from gene to transcript to polypeptide (e.g. ‘missense variant’, ‘frameshift variant’). Note that annotations about variant impact on gene product function, which may occur downstream of a molecular consequence, are not in scope here. These are covered by a Variant Functional Impact Proposition classes.

Information Model

Some VariantMolecularConsequenceProposition attributes are inherited from Subject Variant Proposition.

Field	Flags	Type	Limits	Description
id		string	0..1	The ‘logical’ identifier of the Entity in the system of record, e.g. a UUID. This ‘id’ is unique within a given system, but may or may not be globally unique outside the system. It is used within a system to reference an object from another.
type		string	1..1	MUST be “VariantMolecularConsequenceProposition”.
name		string	0..1	A primary name for the entity.
description		string	0..1	A free-text description of the Entity.
aliases	⋮	string	0..m	Alternative name(s) for the Entity.
extensions	⋮	Extension	0..m	A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model.
subject		Allele | Adjacency | iriReference	1..1	MUST be a genomic variant specified against genomic reference sequence(s). This practice most directly reflects data conventions from sources like VEP, and aligns with the intended use of Molecular Consequence data. There are separate qualifier attributes in the model to capture transcript and/or protein level representations of the subject, that indicate the variant context in which the reported consequence(s) are actually manifest.
predicate		string	1..1	The relationship the Proposition describes between the subject variant and object consequence terms for which the molecular consequence applies. MUST be “hasMolecularConsequence”.
object		Mappable Concept | Concept Set | iriReference	1..1	The molecular consequence(s) of the subject variant, in the context of the qualifying transcript and/or protein variation context(s). These are typically terms from the ‘structural_variant’ branch of the Sequence Ontology, e.g. ‘SO:0001627’ (intron_variant), or ‘SO:0001589’ (frameshift_variant). If more than one consequence term apply, use a ConceptSet to capture them.
transcriptVariationContextQualifier		Allele | Adjacency | iriReference	0..1	The subject genomic variant as projected on a particular transcript or mRNA molecule. The reported relationship between the subject variant and object consequence terms holds specifically in the context of this transcript variation. A transcript variation context MUST be reported, unless the subject is an intergenic variant.
proteinVariationContextQualifier		Allele | Adjacency | iriReference	0..1	The subject genomic variant as projected on a particular protein molecule. The reported relationship between the subject variant and object consequence terms holds specifically in the context of this protein variation. A protein variation context MUST be accompanied by its corresponding transcript variation context.
geneContextQualifier		Mappable Concept | iriReference	0..1	The gene for which this statement reports a VariantMolecularConsequence.

Inherits: Subject Variant Proposition