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 GKS

Will use VA-Spec to represent GKS-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)

Warning

This data class is at a draft maturity level and may change significantly in future releases. Maturity levels are described in the maturity-model.

Computational Definition

A Statement describing the role of a variant in causing an inherited condition.

Information Model

This profile applies the following constraints on top of the core Statement class definition:

Field

Flags

Type

Limits

Description

proposition

Variant Pathogenicity 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.

strength

Mappable Concept (nested enum: likely | definitive)

0..1

A term used to report the strength of a Proposition’s assessment in the direction indicated (i.e. how strongly supported or disputed the Proposition is believed to be). The indicated enumeration is bound to the ‘code’ field in the Coding object nested inside the MappableConcept.

classification

Mappable Concept (nested enum: pathogenic | likely pathogenic | benign | likely benign | uncertain significance)

0..1

A single term or phrase summarizing the outcome of direction and strength assessments of a Statement’s Proposition, in terms of a classification of its subject. The indicated enumeration is bound to the ‘code’ field in the Coding object nested inside the MappableConcept.
Artifacts

Variant Pathogenicity Evidence Line (ACMG 2015)

Warning

This data class is at a draft maturity level and may change significantly in future releases. Maturity levels are described in the 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

This profile applies the following constraints on top of the core Evidence Line class definition:

Field

Flags

Type

Limits

Description

targetProposition

Variant Pathogenicity Proposition

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.

directionOfEvidenceProvided

string (enum: supports | disputes | none)

1..1

The direction of support that the Evidence Line is determined to provide toward its target Proposition (supports, disputes, neutral). For ACMG-based assessments, if a pathogenicity criterion is ‘met’ in the Evidence Line the direction is ‘supports’, if a benignity criterion is ‘met’ the direction is ‘disputes’, and if a criteria is ‘not met’ the direction is ‘none’.

strengthOfEvidenceProvided

Mappable Concept (nested enum: stand alone | very strong | strong | moderate | supporting)

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 ‘directionOfEvidenceProvided’ attribute, and captured using a MappableConcept, whose nested ‘code’ field is bound to an enumerated set of values. Conditional requirement: if directionOfEvidenceProvided is either ‘supports’ or ‘disputes’, then this attribute is required. If it is ‘none’, then this attribute is not allowed.

specifiedBy

Method

0..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).

methodType

string (enum: PVS1 | PS1 | PS2 | PS3 | PS4 | PM1 | PM2 | PM3 | PM4 | PM5 | PM6 | PP1 | PP2 | PP3 | PP4 | PP5 | BA1 | BS1 | BS2 | BS3 | BS4 | BP1 | BP2 | BP3 | BP4 | BP5 | BP6 | BP7)

1..1

A term representing the type of method used to assess evidence for or against the pathogenicity of a variant. Method type is reported as the ACMG Code that defines criteria against which evidence is assessed to determine if it supports pathogenicity or benignity of a variant.

evidenceOutcome

Mappable Concept (nested enum, examples: PS3 | PS3_moderate | PS3_not_met | BP6 | BP6_strong | BS3_not_met)

0..1

The evidence outcome provides a single string that summarizes ‘directionOfEvidenceProvided’ and ‘strengthOfEvidenceProvided’ 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 criterion is not met, the outcome is the criterion code plus the string ‘not_met’ (e.g. ‘PS3_not_met’).

Artifacts