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Systematic ACMG/AMP germline variant classification with all 28 criteria (PVS1, PS1-4, PM1-6, PP1-5, BA1, BS1-4, BP1-7) for clinical significance. Produces 5-tier verdict (Pathogenic / Likely Pathogenic / VUS / Likely Benign / Benign) with cited evidence per criterion.
Passed 12 of 16 test cases with the skill, and 12 of 16 without it.
2 fixed14 passed either way3 still failing3 broke
Tokens, turns and time describe resource use, not a dollar price.
One of 2 test cases the skill fixed. Same model, same prompt, with and without the skill.
A missense variant yields a REVEL score of 0.08 and CADD score of 8. No other evidence is available. How should computational predictions be classified under ACMG rules?
| Checked | Without skill | With skill |
|---|---|---|
| Activates BP4 based on the REVEL score falling below 0.15. | Missed | Passed |
The instructions your model reads when the skill loads.
Each criterion (PS, PM, PP for pathogenic; BS, BP for benign) contributes a weighted piece of evidence for or against pathogenicity. The classification is the COMBINATION of all activated criteria, not any single criterion. Do not overweight a single finding.
The hierarchy is: PVS1 (very strong) > PS (strong) > PM (moderate) > PP (supporting). On the benign side: BA1 (stand-alone) > BS (strong) > BP (supporting). A frameshift in a LOF-intolerant gene (PVS1) plus a ClinVar expert-panel pathogenic entry (PS1) is pathogenic. A single PP criterion alone is not. The combination rule is what matters.
Two common errors to avoid: (1) seeing a "Pathogenic" ClinVar entry and stopping — that is PP5 (supporting) unless it has expert-panel review, not automatic confirmation; (2) dismissing a variant because one predictor says "tolerated" — discordant predictors mean neither PP3 nor BP4 applies, which is neutral evidence, not benign evidence.
Always apply criteria conservatively. When evidence is ambiguous, leave the criterion unmet. Cite the source for every criterion you activate so clinicians can audit the reasoning.
KEY PRINCIPLES:
When uncertain about any scientific fact, SEARCH databases first (PubMed, UniProt, ChEMBL, ClinVar, etc.) rather than reasoning from memory. A database-verified answer is always more reliable than a guess.
test cases passed, vs 12 / 16 without
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