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. If a predisposing evidence type is selected, the clinical significance options include pathogenic, likely pathogenic, benign, likely benign, and uncertain significance. Selection of the clinical significance for predisposing evidence types should align with the 5-tiered pathogenicity scale outlined by ACMG guidelines. (Richards et al. 2015) Finally, a functional evidence type should be associated with one of the following clinical significances: gain of function, loss of function, unaltered function, neomorphic, or unknown. These options allow curators to indicate how the variant impacts the biological function described in the evidence statement.

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

Pathogenic

Very strong evidence the variant is pathogenic

Likely Pathogenic

Strong evidence (>90% certainty) the variant is pathogenic.

Benign

Very strong evidence the variant is benign

Likely Benign

Not expected to have a major effect on disease

Uncertain Significance

Does not fullfill the ACMG criteria for pathogenic/benign, or the evidence is conflicting

Clinical Significance for Functional Evidence

Significance

Symbol

Definition

Gain of Function

A sequence variant whereby new or 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

TBD

Unknown

A functional variant that cannot be precisely defined by gain-of-function, loss-of-function, or unaltered function