Significance¶
Significance describes how the variant is related to a specific, clinically-relevant property as described in the Evidence Statement. Significance terms vary depending on the Evidence Type (e.g. “Resistance” for Predictive Evidence, “Better Outcome” for Prognostic Evidence, etc.).
Understanding Significance¶
The available options for Significance depend on the Evidence Type selected for the Evidence statement. If a Predictive Evidence Type is selected, Significance can include: Sensitivity/Response, Resistance, Adverse Response, Reduced Sensitivity, or N/A. Each of these refers to the association between the Molecular Profile and clinical or preclinical response of the therapeutic(s). If a Diagnostic Evidence Type is selected, the Significance can be either Positive or Negative. A Positive Diagnostic Evidence Item implies that the Molecular Profile is associated with diagnosis of disease or disease subtype whereas a Negative Diagnostic Evidence Item implies lack of association. If a Prognostic Evidence Type is selected, the Significance options include: Better Outcome, Poor Outcome, or N/A. The N/A option can be used to imply that the variant does not have an impact on patient prognosis. A Functional Evidence Type should be associated with one of the following Significance values: Gain of Function, Loss of Function, Unaltered Function, Neomorphic, Dominant Negative, or Unknown. These options allow curators to indicate how the variant impacts the biological function described in the Evidence Statement. Predisposing and Oncogenic Evidence use the Significance values Predisposition/Oncogenicity and Protectiveness. However, final classification of the Significance for these Evidence Types should be established at the assertion level using the appropriate guidelines.
Significance for Predictive Evidence
Significance |
Symbol |
Definition |
---|---|---|
Sensitivity/Response |
Associated with a clinical or preclinical response to treatment |
|
Reduced Sensitivity |
Response to treatment is lower than seen in other treatment contexts |
|
Resistance |
Associated with clinical or preclinical resistance to treatment |
|
Adverse Response |
Associated with an adverse response to drug treatment |
|
N/A |
Variant does not inform clinical interepretation |
Significance for Diagnostic Evidence
Significance |
Symbol |
Definition |
---|---|---|
Positive |
Associated with diagnosis of disease or subtype |
|
Negative |
Associated with lack of disease or subtype |
Significance for Prognostic Evidence
Significance |
Symbol |
Definition |
---|---|---|
Better Outcome |
Demonstrates better than expected clinical outcome |
|
Poor Outcome |
Demonstrates worse than expected clinical outcome |
|
N/A |
Variant does not inform clinical action |
Significance for Predisposing Evidence
Significance |
Symbol |
Definition |
---|---|---|
Predisposition |
Evidence may contribute to an interpretation of pathogenic/benign at the assertion level |
|
Protectiveness |
Presence of a germline molecular profile reduces the chance of cancer |
Significance for Oncogenic Evidence
Significance |
Symbol |
Definition |
---|---|---|
Oncogenicity |
Evidence may contributes to an interpretation of oncogenic/benign at the assertion level |
|
Protectiveness |
Presence of a somatic molecular profile reduces the chance of cancer |
Significance for Functional Evidence
Significance |
Symbol |
Definition |
---|---|---|
Gain of Function |
A sequence variant whereby enhanced function is conferred on the gene product |
|
Loss of Function |
A sequence variant whereby the gene product has diminished or abolished function |
|
Unaltered Function |
A sequence variant whereby the function of the gene product is unchanged |
|
Neomorphic |
Sequence variant creates a novel function |
|
Dominant Negative |
Sequence variant abolishes wild type allele function |
|
Unknown |
A functional variant that cannot be precisely defined by gain-of-function, loss-of-function, or unaltered function |