Curation Methodology

Decision Matrix: Gene Variants

The curation methodology for assigning a protein effect to a gene variant is based on the criteria listed below for each type of effect.

Gain of Function
(Activating)
Peer-reviewed published literature demonstrating functional evidence that the gene alteration present results in increased INTRINSIC activity of the protein.
Gain of Function - Predicted
(Inferred Activating)
The specific type of gene alteration as well as its location is similar to other alterations in the same gene that have been functionally characterized as a gain of function within peer-reviewed published literature.
Loss of Function
Peer-reviewed published literature demonstrating functional evidence that the gene alteration present results in decreased INTRINSIC activity of the protein.
Loss of Function - Predicted
(Inferred Inactivating)
The specific type of gene alteration as well as its location is similar to other alterations in the same gene that have been functionally characterized as a loss of function within peer-reviewed published literature. If all known functional domains or a key domain (i.e. protein kinase domain) are lost, is also appropriate.
No Effect
(Benign)
Peer-reviewed published literature demonstrating functional evidence that the gene alteration present results in activity similar to that of wild-type and does not demonstrate tumorigenic attributes.
Unknown
There is no peer-reviewed published literature demonstrating the gene alteration present affects the intrinsic activity of the protein.

Decision Matrix: Types of Evidence

The curation methodology used to classify evidence is based on the definition and required criteria listed below for each evidence type.

Actionable Actionable evidence is clinical or preclinical data supporting a connection between a molecular profile and a drug response, which is also referred to as "predictive" in the literature. The related response type may be sensitive or resistant.
Diagnostic Diagnostic evidence connects a gene variant or category of variant to the diagnosis of a disease and is supported by either Guidelines, two meta-analyses, or four peer-reviewed published studies.
Prognostic Prognostic evidence connects a gene variant or category of variant with disease outcome and is supported by either Guidelines, a meta-analysis, a review article, or three peer-reviewed published studies.
Risk Factor
Risk factor evidence connects a germline variant or category of variant to the risk of disease onset and is supported by either Guidelines, a meta-analysis, a review article, or three peer-reviewed published studies.
Emerging Emerging provides evidence for potential development of a gene variant as a future cancer therapy target.
Not Active Not Active indicates a particular therapy is no longer involved in any clinical trials and has no other available efficacy evidence.

Decision Matrix: Response Types

The curation methodology used to classify evidence response type is based on the definition and required criteria listed below for each response type.

Sensitive Peer-reviewed published literature demonstrating evidence that a specific gene variant is sensitive to a monotherapy or combination therapy.
Predicted-Sensitive Peer-reviewed published literature demonstrating evidence that an unspecified variant or pathway is sensitive to a monotherapy or combination therapy. If the drug has a specific target or is weakly connected to a target is also appropriate as well as evidence described as preliminary or modest.
Resistant Peer-reviewed published literature demonstrating evidence and specifying that a gene variant is resistant to a specific monotherapy or combination therapy.
Predicted-Resistant Peer-reviewed published literature demonstrating evidence that a category of variant or pathway is resistant to a specific monotherapy or combination therapy. If the evidence described suggests potential resistance, is also appropriate.
Decreased Response Peer-reviewed published literature demonstrating evidence that treatment with a specific monotherapy or combination therapy results in a decreased response when in the context of a specific gene variant.
Conflicting Peer-reviewed published literature from more than one study demonstrating conflicting evidence that a gene variant is or is not sensitive to a specific monotherapy or combination therapy.
No Benefit Peer-reviewed published literature demonstrating evidence that a specific monotherapy or combination therapy does not benefit a particular tumor type. Evidence demonstrating a gene variant or category of variant does not respond to a specific monotherapy or combination therapy.
Not Applicable Evidence types including emerging, diagnostic, and prognostic. Peer-reviewed published literature demonstrating evidence that a monotherapy or combination therapy results in a response, but is not specific to a gene variant or category of variant (defined as Unknown unknown), is also appropriate.