Documentation / Phenotype Matching / Clinical Tiers
Phenotype-Aware Clinical Tiers
The tier answers how strongly a variant should be prioritized for this patient's selected phenotype. It is separate from the variant's ACMG classification and combines phenotype relevance with variant evidence and inheritance context.
Tier Definitions
A rare Pathogenic or Likely Pathogenic variant with a phenotype match of at least 50, subject to inheritance safeguards.
A rare HIGH or MODERATE impact VUS with a phenotype match of at least 70 and no strong benign evidence, or a Tier 1 candidate demoted because the observed inheritance is insufficient.
A rare Pathogenic or Likely Pathogenic variant whose phenotype match is below the Tier 1 threshold. Review separately from referral-phenotype candidates.
A VUS with moderate phenotype and impact support, or a result retained conservatively by a service safeguard.
Benign, Likely Benign, common, or otherwise weakly supported results for the current phenotype.
IF Is Not an ACMG Secondary Findings Determination
The IF group means that a P/LP result does not sufficiently match the referral phenotype. It does not by itself determine reportability, consent scope, or membership in an ACMG Secondary Findings gene list. Apply the appropriate laboratory policy and current professional guidance separately.
Current Assignment Rules
Tier 1 pathway
P/LP, population frequency below 1%, and phenotype match at or above 50. A heterozygous result in an autosomal recessive-only gene is moved to Tier 2 when a second candidate allele is not identified.
Tier 2 pathway
A rare HIGH or MODERATE impact VUS requires phenotype match at or above 70 and must not carry strong benign evidence. Tier 2 is limited to the 15 highest-priority results; overflow is retained in Tier 3 with a recorded reason.
IF pathway
A rare P/LP result below the phenotype threshold is separated from phenotype-relevant Tier 1 results.
Tier 3 pathway
A HIGH or MODERATE impact VUS with phenotype match at or above 30, or another rare VUS with phenotype match at or above 50.
Tier 4 pathway
Benign or Likely Benign classifications, population frequency at or above 1%, reviewed benign ClinVar evidence, and results that do not meet a higher-tier rule.
Additional Safeguards
Inheritance-aware review
Autosomal recessive carrier status can prevent a P/LP result from appearing as immediately actionable. Genes with both dominant and recessive inheritance retain an explanatory note.
Benign evidence
Confirmed benign ClinVar evidence and strong benign ACMG evidence prevent unsupported promotion.
Highly polymorphic regions
HLA-gene results are handled conservatively and do not enter Tier 1 or Tier 2 through this workflow.
Within-tier ordering
Phenotype match, ACMG class, and population rarity order results inside a tier without overriding the tier's clinical safeguards.
Learn how the two 0-100 values differ in Interpreting Scores.