Table 1 Criteria for considering genes for the SF list.

From: Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Variable

Favorable

Unfavorable

Technical (detection at gene level)

Relevant variants routinely detectable on standard clinical ES/GS (without requiring customization of the laboratory methods)

Technical limitations prevent/severely limit the ability to detect the majority of P/LP variation (e.g., would require detection of noncoding variants, construction of haplotypes, or detection of CNVs that are not part of routine ES/GS workflow)

Additional clinical or laboratory testing (excluding orthogonal sequencing test)

Additional approaches for a clinical (e.g., diagnostic imaging) and/or laboratory (e.g., biochemical test) diagnosis are available once the SF is reported

Additional approaches for a clinical and/or laboratory diagnosis are not available.

Clinical presentation

Clinically silent prior to high morbidity or mortality. Onset of signs and symptoms are acute, and presence of risk may be unknown to the individual prior to onset of the symptoms or medical event.

Preventative measures and/or treatments are available and/or individuals with P variants might be asymptomatic for a long time.

Onset may occur in children and/or adults

A condition that presents with signs and/or symptoms in early stages of the disease that, even if they are nonspecific, should prompt a diagnostic workup, potentially to include genetic testing.

Morbidity and mortality

Higher morbidity and/or mortality, and/or disorders in which earlier detection reduces long-term mortality

Lower morbidity and/or mortality

Penetrance

Conditions with higher lifetime penetrance

Conditions with lower, uncertain, or unknown lifetime penetrance

Actionability

A medical intervention is available (e.g., medical or surgical intervention, surveillance). Also, cost of intervention, and patient access, is not considered.

Lifestyle changes (e.g., avoidance of smoking), are not considered medical interventions as defined here. Extreme burden of intervention may be considered unfavorable.

  1. We consider both childhood- and adult-onset phenotypes. Disease prevalence is not a deciding factor (actionable conditions are considered regardless of rarity). The existence of clinical practice guidelines is not considered. Genes are included when the ACMG Secondary Findings Maintenance Working Group (SFWG) reached a consensus.
  2. CNV copy-number variant, ES/GS exome or genome sequencing, P/LP pathogenic/likely pathogenic, SF secondary findings.
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