Tldr
Medically actionable secondary findings are genetic variants discovered during genome or exome sequencing that are unrelated to the original indication but may indicate substantial risk for preventable or treatable monogenic disease. 1
Core Idea
- The American College of Medical Genetics and Genomics publishes recommendations for reporting secondary findings from clinical exome and genome sequencing.1
- ACMG SF v3.2 includes 81 genes associated with treatable or preventable monogenic diseases.1
- In most ACMG SF genes, pathogenic and likely pathogenic variants are considered reportable; exceptions include TTN, where only truncating variants are reportable, and HFE, where only rs1800562 is reportable.1
Russian Population Example
- Suvorova et al. 2026 found ACMG SF v3.2 secondary findings in 2.76% of 42,826 healthy Russian NGI participants.1
- Cancer-associated findings were most common, followed by cardiovascular findings.1
- The most frequent secondary-finding genes in that cohort were BRCA1, BRCA2, RYR1, and LDLR.1
- Candidate pLOF (predicted loss-of-function) variants not yet in ClinVar could increase the estimated frequency if confirmed, but they require orthogonal validation before clinical interpretation.1
Interpretation Caveat
Secondary-finding frequencies depend on the ACMG gene-list version, ClinVar release, variant-calling strategy, structural-variant inclusion, ancestry composition, and clinical return policy. Comparisons across cohorts should therefore treat the reported percentage as pipeline- and policy-dependent, not as a fixed biological constant.2
Related
- Suvorova et al. 2026
- National Genetic Initiative Russia
- Russian Ancestry Groups: Phenotype, Blood, Immunity, and Disease Differences
Sources
- Suvorova et al. 2026, https://doi.org/10.3390/ijms27125344