Variant of uncertain significance

A genetic variant whose relationship to disease is not sufficiently established for confident clinical interpretation. Its classification can change as evidence accumulates.

ACMG/AMP variant interpretation guidelines: A framework for classifying Mendelian genetic variants using evidence of pathogenicity and benignity. These guidelines define the evidence categories laboratories use to assess uncertain variants.
Genetic counseling: A process that helps people understand genetic information, its limits, and its implications. Counseling explains why this result is not a diagnosis and discusses appropriate follow-up.
Pathogenic variant: A genetic variant with sufficient evidence that it causes or contributes to disease. Unlike an uncertain variant, a pathogenic classification supports a disease-related interpretation.
Variant of unknown significance disclosure: Communication of an uncertain genetic finding and its limits to the person tested. Clear disclosure prevents the result from being mistaken for a confirmed diagnosis.
Variant classification: The process of assigning a genetic variant a clinical category based on available evidence. A variant of uncertain significance is one outcome of this broader classification process.
Clinical genetic testing: Testing that examines DNA to inform diagnosis, risk assessment, or medical care. Uncertain classifications commonly arise when clinical tests detect variants with incomplete evidence.
Benign variant: A genetic variant supported by evidence as not causing disease. A benign classification resolves the question that remains open for an uncertain variant.
Overdiagnosis: The identification of a condition that would not have caused symptoms or harm during a person's life. Misreading an uncertain variant as disease-causing can prompt unnecessary diagnosis and intervention.
Population genetics: The study of genetic variation within and between populations. Population frequency can support benignity, but reference databases may underrepresent some ancestries.
Cascade testing: Genetic testing of relatives after a disease-associated variant is identified in a family. Testing relatives solely for an uncertain variant may not provide clinically reliable predictions.

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