Variant Classification

Key facts

Standard framework

ACMG/AMP standards (Richards et al., Genetics in Medicine, 2015)

Number of germline tiers

Five

Meaning of "likely"

Proposed as greater than 90% certainty

Evidence criteria

28 criteria, from PVS1 to BP7

Legal status

Professional society standard, not a federal regulation

What is variant classification?

When a test finds a genetic variant, someone has to decide what it means. Variant classification weighs population frequency, computational predictions, functional studies, segregation in families and published cases to place the variant in a defined category.

In 2015 the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published joint standards for germline variants in Mendelian disease. These standards are used by most U.S. clinical laboratories and by ClinVar.

The five ACMG/AMP classification tiers

Germline variants are placed in one of five categories:

• Pathogenic: evidence establishes that the variant causes disease.
• Likely pathogenic: greater than 90% certainty that the variant causes disease.
• Uncertain significance: evidence is insufficient or conflicting.
• Likely benign: greater than 90% certainty that the variant is benign.
• Benign: evidence establishes that the variant does not cause disease.

How evidence criteria are combined

Pathogenic evidence is weighted very strong (PVS1), strong (PS1 to PS4), moderate (PM1 to PM6) or supporting (PP1 to PP5). Benign evidence is stand-alone (BA1), strong (BS1 to BS4) or supporting (BP1 to BP7). Combining rules turn the criteria that apply into a final tier.

The Clinical Genome Resource (ClinGen) has refined how several criteria are applied, and ClinGen variant curation expert panels publish gene-specific rules. Somatic variants in cancer use separate frameworks: the AMP/ASCO/CAP four-tier clinical impact system and the ClinGen/CGC/VICC oncogenicity scale.

Why variant classification matters

Classifications change as evidence accumulates, and two laboratories can reach different tiers for the same variant. In ClinVar, each submitted classification sits beside a review status from zero stars (no assertion criteria provided) to four stars (practice guideline), with three stars for an expert panel. Anyone counting pathogenic variants for market sizing, trial eligibility or test design should record the classification date, the submitter and the star level, not just the tier.