Using the Variant Classifier¶
The AIVA Variant Classifier is a public tool for classifying variants according to ACMG/AMP guidelines. No login is required.
The classifier follows the ACMG/AMP framework as described in the 2015 joint consensus recommendation:
Richards S, Aziz N, Bale S, et al. "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology." Genet Med. 2015;17(5):405-424.
For the full criteria definitions, refer to the original publication or the ClinGen Sequence Variant Interpretation resources.
Gene-specific guidelines
Several genes and gene groups have published modifications to the standard ACMG/AMP criteria (e.g., TP53, RASopathy genes, CDH1, PTEN). When available, gene-specific guidelines should take precedence over the general framework.
Step 1: Access the Classifier¶
Navigate to the Variant Classifier from the AIVA homepage or public navigation menu. The classifier is accessible without an account.
Step 2: Enter Variant Information¶
Provide information about the variant you want to classify:
- Gene: The gene symbol (e.g., BRCA1, TP53, MLH1).
- Variant notation: HGVS coding or protein notation (e.g., c.5266dupC, p.Gln1756Profs*74).
- Genomic coordinates (optional): Chromosome, position, reference allele, and alternate allele.
- Transcript (optional): The reference transcript identifier (e.g., NM_007294.4).
Variant identifiers
You can enter the variant in any commonly used format. The classifier accepts HGVS nomenclature, genomic coordinates (GRCh37 or GRCh38), and rsIDs.
Step 3: Select ACMG/AMP Criteria¶
The classifier presents the full list of ACMG/AMP evidence criteria organized by type:
Pathogenic Criteria¶
| Category | Criteria | Description |
|---|---|---|
| Very Strong | PVS1 | Null variant in a gene where loss of function is a known mechanism of disease |
| Strong | PS1--PS4 | Same amino acid change, functional studies, segregation, prevalence in affected |
| Moderate | PM1--PM6 | Hot spot, absent from controls, protein length change, novel missense, assumed de novo, in-frame in non-repeat |
| Supporting | PP1--PP5 | Co-segregation, computational, phenotype specificity, reputable source, missense in low-rate gene |
Benign Criteria¶
| Category | Criteria | Description |
|---|---|---|
| Stand-Alone | BA1 | Allele frequency above 5% in population databases |
| Strong | BS1--BS4 | Frequency greater than expected, observed in healthy adults, functional studies, lack of segregation |
| Supporting | BP1--BP7 | Missense in truncation gene, observed in trans, in-frame in benign region, computational, synonymous, reputable source |
For each criterion:
- Review the criterion description to determine whether it applies to your variant.
- Click the criterion to select or deselect it.
- Selected criteria are highlighted and contribute to the classification calculation.
Step 4: Review the Classification¶
As you select criteria, the classifier automatically calculates the classification in real time. The current classification is displayed prominently: Pathogenic, Likely Pathogenic, VUS, Likely Benign, or Benign.
Step 5: Document Your Reasoning (Optional)¶
The classifier allows you to add notes for each selected criterion, documenting the evidence that supports your selection. This is optional for the public tool but recommended for thorough variant interpretation.
Tips for Accurate Classification¶
- Apply criteria conservatively: Only select a criterion when the evidence clearly supports it.
- Use multiple evidence types: A robust classification draws on population data, computational predictions, functional studies, and clinical observations.
- Consider conflicting evidence: If both pathogenic and benign criteria apply, the variant may be classified as VUS pending additional evidence.
Classification responsibility
The Variant Classifier is a decision-support tool. Clinical variant classifications should be performed by qualified professionals in the context of established laboratory protocols and clinical information.