Defining pathogenicity of genetic variants
The ACMG/AMP five-tier system for germline variants, the evidence types behind it, the points-based scoring that labs now use, and what a variant of uncertain significance means for the patient and family.
Tier 2Medical sciences concept
Written with AI assistance and fact-checked against the sources below. For exam study, not clinical decisions. How notes are made
At a glance
- Every genome carries 4 to 5 million variants (see polymorphism and mutation for the terms). Classification asks one question: does this variant cause this disease?
- The 2015 ACMG/AMP standard sorts germline variants into five classes: pathogenic, likely pathogenic, VUS, likely benign, benign. "Likely" means over 90% certainty.
- Classification combines evidence of different types and strengths. ClinGen working groups have refined the criteria for many genes, and most labs now score them as points.
Loading the rest of the note…
Finished reading?
Sources
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMPGenetics in Medicine (Richards et al., 2015;17:405-24), 2015
- Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelinesHuman Mutation (Tavtigian et al., 2020;41:1734-7), 2020
- Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterionHuman Mutation (Abou Tayoun et al., ClinGen SVI, 2018;39:1517-24), 2018
- Standards and guidelines for the interpretation and reporting of sequence variants in cancerJournal of Molecular Diagnostics (Li et al., AMP/ASCO/CAP, 2017;19:4-23), 2017
- Challenges and approaches to genetic variants of uncertain significance in clinical practice and researchGenome Medicine (Li et al., 2026;18:173), 2026
- Shariant variant sharing platformAU/NZAustralian Genomics
- Last updated
- 14 November 2026
What changed
- 14 November 2026 Deploy to Cloudflare on push to main