ACMG 2015 Aligned Profiles
The following profiles align with terminology and curation conventions from the ACMG 2015 Pathogenicity Interpretation Guidelines.
These initial profiles were developed to support the following implementations and use cases:
Implementer |
Use Case |
|---|---|
ClinVar GKM |
Will use VA-Spec to represent GKM-based representations of the ClinVar XML records, and exchange this data across various ClinGen data systems |
MAVE DB |
Will use VA-Spec as a format to send multiplex-assay based functional impact data, classifications, and evidence interpretations to external platforms where they can be used to support pathogenicity and oncogenicity interpretation. |
The number and coverage of these profiles will grow as these implementations expand their scope, and additional adopters bring new use cases to the spec.
Variant Pathogenicity Statement (ACMG 2015)
Draft
May change significantly in future releases. See Maturity Model.
Computational Definition
A Statement describing the role of a variant in causing an inherited condition.
Information Model
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 “Statement”. |
|
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 |
⋮ | 0..m |
A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model. |
|
specifiedBy |
1..1 |
The method that specifies how the pathogenicity classification is ultimately assigned to the variant, based on assessment of evidence. |
||
contributions |
↓ | 0..m |
Specific actions taken by an Agent toward the creation, modification, validation, or deprecation of an Information Entity. |
|
reportedIn |
⋮ | 0..m |
A document in which the the Information Entity is reported. |
|
proposition |
1..1 |
A proposition about the pathogenicity of a variant, the validity of which is assessed and reported by the Statement. A Statement can put forth the proposition as being true, false, or uncertain, and may provide an assessment of the level of confidence/evidence supporting this claim. |
||
direction |
string |
0..1 |
A term indicating whether the Statement supports, disputes, or remains neutral w.r.t. the validity of the Proposition it evaluates. |
|
strength |
0..1 |
The strength of support that an ACMG 2015 Variant Pathogenicity statement is determined to provide for or against the proposed pathogenicity of the assessed variant. Strength is evaluated relative to the direction indicated by the ‘direction’ attribute. The indicated enumeration constrains the nested MappableConcept.primaryCoding > Coding.code attribute when capturing evidence strength. |
||
quality |
D | 0..1 |
A term used to report the quality of the assessment of a Proposition taking into consideration the reliability of the method, the contributor’s self-reporting of the rigor of the evaluation, and the overall robustness of the supporting or disputing evidence. This is useful when there is a consistent policy and authority that manages and a governing framework for evaluating the quality of evidence. Also known as trust rating, review status or ranking. |
|
score |
D | number |
0..1 |
A quantitative score that indicates the strength of a Proposition’s assessment in the direction indicated (i.e. how strongly supported or disputed the Proposition is believed to be). Depending on its implementation, a score may reflect how confident that agent is that the Proposition is true or false, or the strength of evidence they believe supports or disputes it. Instructions for how to interpret the meaning of a given score may be gleaned from the method or document referenced in ‘specifiedBy’ attribute. |
classification |
1..1 |
The classification of the variant’s pathogenicity, based on the ACMG 2015 guidelines. These classifications should coincide with the direction and strength values as follows: ‘pathogenic’ with supports-strong, ‘likely pathogenic’ with supports-moderate, ‘benign’ with disputes-strong, ‘likely benign’ with disputes-moderate ‘uncertain significance’ can be one of three possibilities… supports-weak, disputes-weak or neutral for uncertain significance (favoring pathogenic), uncertain significance (favoring benign) or uncertain significance (favoring neither pathogenic nor benign). The ‘low penetrance’ and ‘risk allele’ versions of pathogenicity classifications would be applied based on whether the variant proposition was defined to have a ‘penetrance’ of ‘low’ or ‘risk’ respectively. |
||
hasEvidence |
⋮ | 0..m |
An individual piece of information that was evaluated as evidence in assessing the validity of the Proposition put forth by the Statement. |
|
hasEvidenceLines |
⋮ | Variant Pathogenicity Evidence Line (ACMG 2015) | iriReference |
0..m |
An evidence-based argument that supports or disputes the validity of the proposition that a Statement assesses or puts forth as true. The strength and direction of this argument (whether it supports or disputes the proposition, and how strongly) is based on an interpretation of one or more pieces of information as evidence (i.e. ‘Evidence Items). |
Composes: Statement
Variant Pathogenicity Evidence Line (ACMG 2015)
Draft
May change significantly in future releases. See Maturity Model.
Computational Definition
An Evidence Line that describes how a specific type of information was interpreted as evidence for or against a variant’s pathogenicity. In the ACMG Framework, evidence is assessed by determining if a specific criterion (e.g. ‘PM2’) with a default strength (e.g. ‘moderate’) is ‘met’ or ‘not met’, and in some cases adjusting the default strength based on the quality and abundance of evidence.
Information Model
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 “EvidenceLine”. |
|
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 |
⋮ | 0..m |
A list of extensions to the Entity, that allow for capture of information not directly supported by elements defined in the model. |
|
specifiedBy |
1..1 |
The guidelines or rubrics followed in interpreting evidence, to determine the strength and direction of support that it provides for or against a variant’s pathogenicity. While the ACMG Criteria themselves provide minimal guidance, typically a more detailed, disease- or gene- specific rubric is followed to determine if a given criterion was met, and how strongly (e.g. the ClinGen Hearing Loss Expert Panel guidelines for ACMG interpretations). |
||
contributions |
↓ | 0..m |
Specific actions taken by an Agent toward the creation, modification, validation, or deprecation of an Information Entity. |
|
reportedIn |
⋮ | 0..m |
A document in which the the Information Entity is reported. |
|
targetProposition |
0..1 |
A Variant Pathogenicity Proposition against which a specific type of evidence was assessed, to determine the strength and direction of support this evidence provides for or against the proposition’s validity. |
||
hasEvidenceItems |
⋮ | 0..m |
An individual piece of information that was evaluated as evidence in building the argument represented by an Evidence Line. |
|
directionOfEvidenceProvided |
string |
1..1 |
The direction of support that the Evidence Line is determined to provide toward its target Proposition (supports, disputes, neutral) |
|
strengthOfEvidenceProvided |
0..1 |
The strength of support that an Evidence Line is determined to provide for or against the proposed pathogenicity of the assessed variant. Strength is evaluated relative to the direction indicated by the ‘direction’ attribute, and captured using a MappableConcept, whose nested ‘code’ field is bound to an enumerated set of values. Conditional requirement: if direction is either ‘supports’ or ‘disputes’, then this attribute is required. If it is ‘neutral’, then this attribute is not allowed. |
||
scoreOfEvidenceProvided |
number |
0..1 |
A quantitative score indicating the strength of support that an Evidence Line is determined to provide for or against its target Proposition, evaluated relative to the direction indicated by the directionOfEvidenceProvided value. |
|
evidenceOutcome |
0..1 |
The evidence outcome provides a single string that summarizes ‘direction’ and ‘strength’ assessments, along with the specific ACMG criterion used in these assessments. Rules for constructing this string are as follows, and enforced by a regex constraint: (1) If a criterion is met and its default strength is not altered, the outcome is simply the criterion code (e.g. ‘PM2’ when the PM2 criteria is met with moderate strength); (2) If a criterion is met and its default strength is altered, the outcome is the criterion code plus the altered strength value (e.g. ‘PS3_moderate’ when PS3 is met with an adjusted moderate strength); (3) If a specific criterion was assessed but not met, the outcome is the criterion code plus ‘_not_met’ (e.g. ‘PS3_not_met’); (4) If the criteria associated with the ‘methodType’ were assessed, but none were met, the outcome is ‘no_criteria_met’. |
Additional Constraints
If property… |
has value… |
then property… |
must… |
|---|---|---|---|
directionOfEvidenceProvided |
one of: supports, disputes |
strengthOfEvidenceProvided |
be provided |
specifiedBy.methodType |
population_data_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(BA1|BS1|PM2)(_.+)?)$ |
specifiedBy.methodType |
case_control_enrichment_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(BS2|PM4)(_.+)?)$ |
specifiedBy.methodType |
null_variant_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|PVS1(_.+)?)$ |
specifiedBy.methodType |
same_amino_acid_change_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|PS1(_.+)?)$ |
specifiedBy.methodType |
mutational_hot_spot_and_functional_domain_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|PM1(_.+)?)$ |
specifiedBy.methodType |
protein_length_change_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PM4|BP3)(_.+)?)$ |
specifiedBy.methodType |
novel_missense_position_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|PM5(_.+)?)$ |
specifiedBy.methodType |
variant_spectrum_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PP2|BP1)(_.+)?)$ |
specifiedBy.methodType |
in_silico_functional_impact_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PP3|BP4)(_.+)?)$ |
specifiedBy.methodType |
predicted_silent_variant_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|BP7(_.+)?)$ |
specifiedBy.methodType |
functional_data_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PS3|BS3)(_.+)?)$ |
specifiedBy.methodType |
segregation_data_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PP1|BS4)(_.+)?)$ |
specifiedBy.methodType |
de_novo_occurrence_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PS2|PM6)(_.+)?)$ |
specifiedBy.methodType |
cis_trans_variant_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PM3|BP2)(_.+)?)$ |
specifiedBy.methodType |
reputable_source_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|(PP5|BP6)(_.+)?)$ |
specifiedBy.methodType |
phenotype_gene_specificity_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|PP4(_.+)?)$ |
specifiedBy.methodType |
alternative_cause_assessment |
evidenceOutcome.primaryCoding.code |
match the pattern ^(?:no_criteria_met|BP5(_.+)?)$ |
If evidenceOutcome.primaryCoding.code must match the pattern ^(?:no_criteria_met|(?:[A-Z]+[0-9]+)_not_met)$, then:
directionOfEvidenceProvided must be: neutral
Composes: Evidence Line
Used in: Variant Pathogenicity Statement (ACMG 2015)
Artifacts