Table 1.

Combination of criteria for variant interpretation according to ACMG-AMP guidelines. The modifications implemented in the internal ACMG-based classifier are underlined.

Pathogenic	(i) 1 Very strong (PVS1) AND (a) ≥1 Strong (PS1–PS4) OR (b) ≥2 Moderate (PM1–PM6) OR (c) 1 Moderate (PM1–PM6) AND at least * 1 Supporting (PP1–PP5) OR (d) ≥2 Supporting (PP1–PP5) OR (e)≥1 Very strong (PVS1) * (ii) ≥2 Strong (PS1–PS4) OR (iii) 1 Strong (PS1–PS4) AND (a)≥3 Moderate (PM1–PM6) OR (b)2 Moderate (PM1–PM6) AND ≥ 2 Supporting (PP1–PP5) OR (c)1 Moderate (PM1–PM6) AND ≥ 4 supporting (PP1–PP5)
Likely Pathogenic	(i) 1 Very strong (PVS1) AND 1 moderate (PM1– PM6) OR (ii) 1 Strong (PS1–PS4) AND 1–2 moderate (PM1–PM6) OR (iii) 1 Strong (PS1–PS4) AND ≥ 2 supporting (PP1–PP5) OR (iv) ≥3 Moderate (PM1–PM6) OR (v) 2 Moderate (PM1–PM6) AND ≥ 2 supporting (PP1–PP5) OR (vi) 1 Moderate (PM1–PM6) AND ≥ 3 supporting (PP1–PP5)
Benign	(i) 1 Stand-alone (BA1) OR (ii) ≥2 Strong (BS1–BS4)
Likely benign	(i) 1 Strong (BS1–BS4) ° OR (ii) ≥2 Supporting (BP1–BP7)
Uncertain significance	(i) Other criteria shown above are not met OR (ii) the criteria for benign and pathogenic are contradictory

* These modifications were added to include the possibility of varying the strength of pathogenic criteria. ° If ONLY a strong benign criterion (BS1–BS4) is triggered together with any pathogenic criterion, the former is not considered in deciding the final verdict.