Clinical Significance¶
Clinical Significance describes how the variant is related to a specific, clinically-relevant property as described in the Evidence Statement.
Understanding Clinical Significance¶
The available options for clinical significance depend on the evidence type selected for the evidence statement. If a predictive evidence type is selected, clinical significance can include: sensitivity/response, resistance, adverse response, reduced sensitivity, or N/A. Each of these refers to the association between the variant and clinical or preclinical response of the therapeutic(s). If a diagnostic evidence type is selected, the clinical significance can be either positive or negative. A positive diagnostic evidence item implies that the variant 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 clinical 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 clinical significances: 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. Note that Predisposing and Oncogenic Evidence do not have an Evidence Direction or Clinical Significance. These should be established at the assertion level using the appropriate guidelines.
Clinical Significance for Predictive Evidence
Significance |
Symbol |
Definition |
---|---|---|
Sensitivity/Response |
Associated with a clinical or preclinical response to treatment |
|
Resistance |
Associated with clinical or preclinical resistance to treatment |
|
Adverse Response |
Associated with an adverse response to drug treatment |
|
Reduced Sensitivity |
Response to treatment is lower than seen in other treatment contexts |
|
N/A |
Variant does not inform clinical action |
Clinical Significance for Diagnostic Evidence
Significance |
Symbol |
Definition |
---|---|---|
Positive |
Associated with diagnosis of disease or subtype |
|
Negative |
Associated with lack of disease or subtype |
Clinical 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 |
Clinical Significance for Predisposing Evidence
Significance |
Symbol |
Definition |
---|---|---|
N/A |
Clinical Significance is only applied at the assertion level |
Clinical Significance for Oncogenic Evidence
Significance |
Symbol |
Definition |
---|---|---|
N/A |
Clinical Significance is only applied at the assertion level |
Clinical 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 |