Actionable Genotypes and Their Association with Life Span in Iceland

This large-scale population study assessed the prevalence and survival implications of actionable genotypes in 73 genes from the ACMG SF v3.0 list among 57,933 Icelanders. Manual curation identified 235 pathogenic or likely pathogenic variants across 53 genes, found in 2306 individuals (4.0%). Carriers of actionable genotypes in cancer genes—especially BRCA2 and BRCA1—had reduced median survival (~3 years shorter) and higher rates of cancer-related mortality. Certain cardiovascular variants (e.g., in LDLR and MYBPC3) also correlated with shortened life span, although effects were less pronounced across the broader cardiovascular group. Notably, returning such genomic findings in population-based cohorts could help mitigate disease burden through targeted prevention. The authors also proposed 10 additional variants for future inclusion on the ACMG list, based on their association with disease and actionable interventions.

This large-scale population study assessed the prevalence and survival implications of actionable genotypes in 73 genes from the ACMG SF v3.0 list among 57,933 Icelanders. Manual curation identified 235 pathogenic or likely pathogenic variants across 53 genes, found in 2306 individuals (4.0%). Carriers of actionable genotypes in cancer genes—especially BRCA2 and BRCA1—had reduced median survival (~3 years shorter) and higher rates of cancer-related mortality. Certain cardiovascular variants (e.g., in LDLR and MYBPC3) also correlated with shortened life span, although effects were less pronounced across the broader cardiovascular group. Notably, returning such genomic findings in population-based cohorts could help mitigate disease burden through targeted prevention. The authors also proposed 10 additional variants for future inclusion on the ACMG list, based on their association with disease and actionable interventions.