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.
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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 Personal emails, About story and Australian-style copy