Table 1. Knowledge Synthesis Team's Stage II methods to generate summary reports.

Systematic Identification of Sources
Clinical practice guidelines, systematic reviews, and meta-analyses OMIM, GeneReviews, and OrphaNet entries Clinical Utility Gene Cards Excluded: Narrative reviews and single-study research papers
Determination of Relevance
Relevant references provide information on actionability in an adult who has not been diagnosed with the genetic condition, though they may be symptomatic of the clinical manifestations associated with the genetic condition Actionability is defined as interventions or treatments that might lead to disease prevention or delayed onset, lowered clinical burden, or improved clinical outcomes
Tier Ratings of Relevant Sources
Tier 1Evidence from a systematic review, a meta-analysis clearly based on a systematic review, or a clinical practice guideline clearly based on a systematic review Tier 2Evidence from clinical practice guidelines or broad-based expert consensus with some level of evidence review, but using unclear methods or sources that were not systematically identified Tier 3Evidence from another source with non-systematic review of evidence (e.g., GeneReviews, OrphaNet, and Clinical Utility Gene Cards, or opinion of up to 4 experts that provides guidance) with primary literature cited Tier 4Evidence from another source with non-systematic review of evidence (e.g., GeneReviews, OrphaNet, and Clinical Utility Gene Cards, or opinion of up to 4 experts that provides guidance) with no citations to primary data sources Tier 5Evidence from a non-systematically identified source (e.g., nominated by an AWG member for inclusion)
Data Abstraction
Evidence with the highest tier is abstracted for 5 aspects of clinical actionability: What is the nature of the threat to health for an individual carrying a pathogenic allele of the given gene? How effective are interventions for preventing harm? What is the chance that this threat will materialize? How acceptable are the interventions in terms of the burdens or risks placed on the individual? Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?