Clinvar Classifications

# Understanding ClinVar Classifications

## What is ClinVar?

ClinVar is a free, public database maintained by the National Center for Biotechnology Information (NCBI). It collects information about genetic variants and their relationship to human health.

## The Five-Tier Classification System

ClinVar uses a standardized five-level system to classify variants:

### 1. Pathogenic
- **Meaning**: Strong scientific evidence that this variant causes or significantly increases risk of disease
- **What to do**: Discuss with a healthcare provider or genetic counselor
- **Important**: Does NOT mean you will definitely develop the condition

### 2. Likely Pathogenic
- **Meaning**: High probability (>90%) that this variant is disease-causing, but evidence isn't quite as strong
- **What to do**: Generally managed the same as pathogenic variants
- **Important**: May be reclassified as more evidence emerges

### 3. Uncertain Significance (VUS)
- **Meaning**: Not enough evidence to determine if this variant is harmful or benign
- **What to do**: Do NOT make medical decisions based on a VUS
- **Important**: Most VUS are eventually reclassified as benign (harmless)

### 4. Likely Benign
- **Meaning**: High probability (>90%) that this variant is harmless
- **What to do**: Generally, no clinical action needed
- **Important**: May be upgraded to fully benign with more evidence

### 5. Benign
- **Meaning**: Strong scientific evidence that this variant does NOT cause disease
- **What to do**: No action needed
- **Important**: This is just normal human variation

## Understanding Review Status

ClinVar also indicates how well-reviewed a classification is:

- **Practice guideline**: Expert panel has reviewed the evidence
- **Reviewed by expert panel**: Multiple experts have assessed the variant
- **Criteria provided, multiple submitters, no conflicts**: Strong agreement among labs
- **Criteria provided, single submitter**: Only one lab has submitted
- **No assertion criteria provided**: Limited evidence available

**Higher review status = more confidence in the classification**

## Important Limitations

1. **Classifications change**: As science advances, variants can be reclassified
2. **Not all variants are in ClinVar**: Absence doesn't mean a variant is benign
3. **Context matters**: The same variant can have different implications depending on the gene and your health history
4. **Not a diagnosis**: ClinVar provides information, not medical diagnoses

## What ClinVar is NOT

- ClinVar is NOT intended for direct diagnostic use
- ClinVar is NOT a substitute for clinical evaluation
- ClinVar does NOT provide personalized medical advice

Always discuss genetic findings with a qualified healthcare provider or genetic counselor.