ACMG classification and clinical significance

The ACMG/AMP guidelines give a standardized 5-tier interpretation for a variant:

Pathogenic
Likely Pathogenic
Variant of Uncertain Significance (VUS)
Likely Benign
Benign

These are derived from weighted evidence criteria (population data, computational predictions, functional studies, segregation).

For a clinical-adjacent product this matters enormously: the system must report the recorded classification and never upgrade/downgrade it on its own.

VUS is the most common and most easily mis-explained — a strong answer notes that "uncertain" is not "benign."