Documentation / Variant Analysis / Combining Rules
ACMG/AMP Evidence Combining Rules
Folklore groups applied criteria by pathogenic or benign direction and by evidence strength. It then evaluates the published ACMG/AMP combinations in a deterministic order, with documented ClinGen strength modifications where applicable.
Rule Families
Pathogenic
P1: 1 Very Strong + at least 1 Strong
P2: 1 Very Strong + at least 2 Moderate
P3: 1 Very Strong + 1 Moderate + 1 Supporting
P4: 1 Very Strong + at least 2 Supporting
P5: at least 2 Strong
P6: 1 Strong + at least 3 Moderate
P7: 1 Strong + 2 Moderate + at least 2 Supporting
P8: 1 Strong + 1 Moderate + at least 4 Supporting
Likely Pathogenic
LP1: 1 Very Strong + 1 Moderate
LP1b: PVS1 or PVS1_Strong + 1 Supporting when an applicable specification downgrades evidence strength
LP2: 1 Strong + 1 or 2 Moderate
LP3: 1 Strong + at least 2 Supporting
LP4: at least 3 Moderate
LP5: 2 Moderate + at least 2 Supporting
LP6: 1 Moderate + at least 4 Supporting
Benign and Likely Benign
B1: 1 Stand-alone benign criterion
B2: at least 2 Strong benign criteria
LB1: 1 Strong benign + 1 Supporting benign
LB2: at least 2 Supporting benign criteria
Safety Guards
A matching evidence count is necessary but not always sufficient. Folklore can hold a result at VUS when evidence is contradictory, when inheritance does not support the proposed mechanism, when a profile relies only on limited computational evidence, or when required clinical context is absent. These guards prevent a mathematically matching combination from being presented as stronger than the available evidence supports.
No hidden point total
The current nuclear classifier records criteria and strength levels and applies rule combinations. It does not expose a general per-variant Bayesian point total as the source of the final class. Calibrated predictor thresholds may modify evidence strength, but the displayed class is produced by the rule hierarchy and its safety checks.