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skills/clinvar-database/references/clinical_significance.md

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+# ClinVar Clinical Significance Interpretation Guide
+
+## Overview
+
+ClinVar uses standardized terminology to describe the clinical significance of genetic variants. Understanding these classifications is critical for interpreting variant reports and making informed research or clinical decisions.
+
+## Important Disclaimer
+
+**ClinVar data is NOT intended for direct diagnostic use or medical decision-making without review by a genetics professional.** The interpretations in ClinVar represent submitted data from various sources and should be evaluated in the context of the specific patient and clinical scenario.
+
+## Three Classification Categories
+
+ClinVar represents three distinct types of variant classifications:
+
+1. **Germline variants** - Inherited variants related to Mendelian diseases and drug responses
+2. **Somatic variants (Clinical Impact)** - Acquired variants with therapeutic implications
+3. **Somatic variants (Oncogenicity)** - Acquired variants related to cancer development
+
+## Germline Variant Classifications
+
+### Standard ACMG/AMP Terms
+
+These are the five core terms recommended by the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP):
+
+| Term | Abbreviation | Meaning | Probability |
+|------|--------------|---------|-------------|
+| **Pathogenic** | P | Variant causes disease | ~99% |
+| **Likely Pathogenic** | LP | Variant likely causes disease | ~90% |
+| **Uncertain Significance** | VUS | Insufficient evidence to classify | N/A |
+| **Likely Benign** | LB | Variant likely does not cause disease | ~90% non-pathogenic |
+| **Benign** | B | Variant does not cause disease | ~99% non-pathogenic |
+
+### Low-Penetrance and Risk Allele Terms
+
+ClinGen recommends additional terms for variants with incomplete penetrance or risk associations:
+
+- **Pathogenic, low penetrance** - Disease-causing but not all carriers develop disease
+- **Likely pathogenic, low penetrance** - Probably disease-causing with incomplete penetrance
+- **Established risk allele** - Confirmed association with increased disease risk
+- **Likely risk allele** - Probable association with increased disease risk
+- **Uncertain risk allele** - Unclear risk association
+
+### Additional Classification Terms
+
+- **Drug response** - Variants affecting medication efficacy or metabolism
+- **Association** - Statistical association with trait/disease
+- **Protective** - Variants that reduce disease risk
+- **Affects** - Variants that affect a biological function
+- **Other** - Classifications that don't fit standard categories
+- **Not provided** - No classification submitted
+
+### Special Considerations
+
+**Recessive Disorders:**
+A disease-causing variant for an autosomal recessive disorder should be classified as "Pathogenic," even though heterozygous carriers will not develop disease. The classification describes the variant's effect, not the carrier status.
+
+**Compound Heterozygotes:**
+Each variant is classified independently. Two "Likely Pathogenic" variants in trans can together cause recessive disease, but each maintains its individual classification.
+
+## Somatic Variant Classifications
+
+### Clinical Impact (AMP/ASCO/CAP Tiers)
+
+Based on guidelines from the Association for Molecular Pathology (AMP), American Society of Clinical Oncology (ASCO), and College of American Pathologists (CAP):
+
+| Tier | Meaning |
+|------|---------|
+| **Tier I - Strong** | Variants with strong clinical significance - FDA-approved therapies or professional guidelines |
+| **Tier II - Potential** | Variants with potential clinical actionability - emerging evidence |
+| **Tier III - Uncertain** | Variants of unknown clinical significance |
+| **Tier IV - Benign/Likely Benign** | Variants with no therapeutic implications |
+
+### Oncogenicity (ClinGen/CGC/VICC)
+
+Based on standards from ClinGen, Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC):
+
+| Term | Meaning |
+|------|---------|
+| **Oncogenic** | Variant drives cancer development |
+| **Likely Oncogenic** | Variant probably drives cancer development |
+| **Uncertain Significance** | Insufficient evidence for oncogenicity |
+| **Likely Benign** | Variant probably does not drive cancer |
+| **Benign** | Variant does not drive cancer |
+
+## Review Status and Star Ratings
+
+ClinVar assigns review status ratings to indicate the strength of evidence behind classifications:
+
+| Stars | Review Status | Description | Weight |
+|-------|---------------|-------------|--------|
+| ★★★★ | **Practice Guideline** | Reviewed by expert panel with published guidelines | Highest |
+| ★★★ | **Expert Panel Review** | Reviewed by expert panel (e.g., ClinGen) | High |
+| ★★ | **Multiple Submitters, No Conflicts** | ≥2 submitters with same classification | Moderate |
+| ★ | **Criteria Provided, Single Submitter** | One submitter with supporting evidence | Standard |
+| ☆ | **No Assertion Criteria** | Classification without documented criteria | Lowest |
+| ☆ | **No Assertion Provided** | No classification submitted | None |
+
+### What the Stars Mean
+
+- **4 stars**: Highest confidence - vetted by expert panels, used in clinical practice guidelines
+- **3 stars**: High confidence - expert panel review (e.g., ClinGen Variant Curation Expert Panel)
+- **2 stars**: Moderate confidence - consensus among multiple independent submitters
+- **1 star**: Single submitter with evidence - quality depends on submitter expertise
+- **0 stars**: Low confidence - insufficient evidence or no criteria provided
+
+## Conflicting Interpretations
+
+### What Constitutes a Conflict?
+
+As of June 2022, conflicts are reported between:
+- Pathogenic/likely pathogenic **vs.** Uncertain significance
+- Pathogenic/likely pathogenic **vs.** Benign/likely benign
+- Uncertain significance **vs.** Benign/likely benign
+
+### Conflict Resolution
+
+When conflicts exist, ClinVar reports:
+- **"Conflicting interpretations of pathogenicity"** - Disagreement on clinical significance
+- Individual submissions are displayed so users can evaluate evidence
+- Higher review status (more stars) carries more weight
+- More recent submissions may reflect updated evidence
+
+### Handling Conflicts in Research
+
+When encountering conflicts:
+1. Check the review status (star rating) of each interpretation
+2. Examine the evidence and criteria provided by each submitter
+3. Consider the date of submission (more recent may reflect new data)
+4. Review population frequency data and functional studies
+5. Consult expert panel classifications when available
+
+## Aggregate Classifications
+
+ClinVar calculates an aggregate classification when multiple submitters provide interpretations:
+
+### No Conflicts
+When all submitters agree (within the same category):
+- Display: Single classification term
+- Confidence: Higher with more submitters
+
+### With Conflicts
+When submitters disagree:
+- Display: "Conflicting interpretations of pathogenicity"
+- Details: All individual submissions shown
+- Resolution: Users must evaluate evidence themselves
+
+## Interpretation Best Practices
+
+### For Researchers
+
+1. **Always check review status** - Prefer variants with ★★★ or ★★★★ ratings
+2. **Review submission details** - Examine evidence supporting classification
+3. **Consider publication date** - Newer classifications may incorporate recent data
+4. **Check assertion criteria** - Variants with ACMG criteria are more reliable
+5. **Verify in context** - Population, ethnicity, and phenotype matter
+6. **Follow up on conflicts** - Investigate discrepancies before making conclusions
+
+### For Variant Annotation Pipelines
+
+1. Prioritize higher review status classifications
+2. Flag conflicting interpretations for manual review
+3. Track classification changes over time
+4. Include population frequency data alongside ClinVar classifications
+5. Document ClinVar version and access date
+
+### Red Flags
+
+Be cautious with variants that have:
+- Zero or one star rating
+- Conflicting interpretations without resolution
+- Classification as VUS (uncertain significance)
+- Very old submission dates without updates
+- Classification based on in silico predictions alone
+
+## Common Query Patterns
+
+### Search for High-Confidence Pathogenic Variants
+
+```
+BRCA1[gene] AND pathogenic[CLNSIG] AND practice guideline[RVSTAT]
+```
+
+### Filter by Review Status
+
+```
+TP53[gene] AND (reviewed by expert panel[RVSTAT] OR practice guideline[RVSTAT])
+```
+
+### Exclude Conflicting Interpretations
+
+```
+CFTR[gene] AND pathogenic[CLNSIG] NOT conflicting[RVSTAT]
+```
+
+## Updates and Reclassifications
+
+### Why Classifications Change
+
+Variants may be reclassified due to:
+- New functional studies
+- Additional population data (e.g., gnomAD)
+- Updated ACMG guidelines
+- Clinical evidence from more patients
+- Segregation data from families
+
+### Tracking Changes
+
+- ClinVar maintains submission history
+- Version-controlled VCV/RCV accessions
+- Monthly updates to classifications
+- Reclassifications can go in either direction (upgrade or downgrade)
+
+## Key Resources
+
+- ACMG/AMP Variant Interpretation Guidelines: Richards et al., 2015
+- ClinGen Sequence Variant Interpretation Working Group: https://clinicalgenome.org/
+- ClinVar Clinical Significance Documentation: https://www.ncbi.nlm.nih.gov/clinvar/docs/clinsig/
+- Review Status Documentation: https://www.ncbi.nlm.nih.gov/clinvar/docs/review_status/