Documentation / Phenotype Matching / Clinical Tiers
Clinical Tiers
After phenotype matching, each variant is assigned to one of five clinical tiers. The tier system answers: "How relevant is this variant to THIS patient's specific phenotype?" -- not "How pathogenic is this variant in general?"
Why Phenotype Relevance Matters
A Pathogenic BRCA1 variant found in a patient referred for epilepsy should not outrank a VUS in SCN1A with strong phenotype match for seizures. The tier system ensures that pathogenic variants without phenotype relevance are flagged as Incidental Findings (IF), not mixed with phenotype-confirmed results. This matches clinical reality where secondary findings must be reported separately.
Tier Definitions
Strong phenotype match combined with a Pathogenic or Likely Pathogenic variant. These variants are both pathogenic and relevant to this patient’s clinical presentation. Immediate clinical review recommended.
VUS with strong supporting evidence -- high functional impact, strong phenotype correlation, or both. Candidates for further investigation through literature search, functional studies, or family segregation.
Pathogenic or Likely Pathogenic variant in a gene that does NOT match the patient’s phenotype. Clinically important (may be reportable per ACMG Secondary Findings guidelines) but represents a different condition than the referral reason.
VUS with moderate evidence. May warrant monitoring but insufficient for clinical action. Review if Tier 1 and Tier 2 do not explain the phenotype.
Low evidence, benign, likely benign, or common variants. Generally not clinically relevant for this patient. Reported in summary counts only.
Score Structure
Each variant receives a clinical priority score (0-100) composed of a tier base score plus a fine score for within-tier ranking. This guarantees non-overlapping score ranges between tiers:
Final Score = Tier Base Score + Fine Score (0 to 19.99)
| Tier | Base Score | Score Range |
|---|---|---|
| Tier 1 - Actionable | 80 | 80.00 - 99.99 |
| Tier 2 - Potentially Actionable | 60 | 60.00 - 79.99 |
| IF - Incidental Finding | 40 | 40.00 - 59.99 |
| Tier 3 - Uncertain | 20 | 20.00 - 39.99 |
| Tier 4 - Unlikely | 0 | 0.00 - 19.99 |
Within-Tier Fine Scoring
Within each tier, the fine score (0-19.99) ranks variants by three weighted components:
Tier Assignment Rules
Tier assignment is rule-based, not purely score-based. The rules combine ACMG classification, population frequency, variant impact, and phenotype match strength:
Always Tier 4
Benign or Likely Benign variants (regardless of phenotype match)
Common variants (gnomAD allele frequency 1% or higher)
Pathogenic / Likely Pathogenic Pathway
P/LP + rare + phenotype match at or above 20% = Tier 1 (Actionable)
P/LP + rare + HIGH impact + phenotype match at or above 5% = Tier 1 (lower threshold for high-impact variants)
P/LP + rare + phenotype match below thresholds = IF (Incidental Finding)
VUS Pathway
VUS + HIGH impact + rare = Tier 2 (Potentially Actionable)
VUS + HIGH or MODERATE impact + phenotype match at or above 70% + rare = Tier 2
VUS + MODERATE or HIGH impact + phenotype match at or above 30% = Tier 3 (Uncertain)
VUS + phenotype match at or above 50% + rare = Tier 3
Everything else = Tier 4 (Unlikely)
Frequency Scoring
Population frequency from gnomAD is converted to a 0-100 score for the fine-scoring component:
| gnomAD AF | Score | Category |
|---|---|---|
| Absent (None or 0) | 100 | Not observed in population |
| < 0.001% | 95 | Ultra-rare |
| < 0.01% | 85 | Very rare |
| < 0.1% | 70 | Rare |
| < 1% | 40 | Uncommon |
| < 5% | 15 | Low frequency |
| 5% or higher | 0 | Common |
For guidance on reading phenotype match scores in practice, see Interpreting Scores.