Fitting a naturally scaled point system to the ACMG/AMP variant
Recently, we demonstrated that the qualitative American College of
Medical Genetics and Genomics/ Association for Medical Pathology
(ACMG/AMP) guidelines for evaluation of Mendelian disease gene variants
are fundamentally compatible with a quantitative Bayesian formulation.
Here, we show that the underlying ACMG/AMP “strength of evidence
categories” can be abstracted into a point system. These points are
proportional to Log(odds), are additive, and produce a system that
recapitulates the Bayesian formulation of the ACMG/AMP guidelines.
Strengths of this system are its simplicity and that the connection
between point values and odds of pathogenicity allows empirical
calibration of strength of evidence for individual data types.
Weaknesses include that a narrow range of prior probabilities is locked
in, and that the Bayesian nature of the system is inapparent. We
conclude that a points-based system has useful attributes of user
friendliness and can be useful so long as the underlying Bayesian
principles are acknowledged.