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Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing



We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR).


Participants (n = 2,535) with hypercholesterolemia and/or colon polyps underwent targeted sequencing of 68 genes and 14 single-nucleotide variants. Penetrance was estimated based on presence of relevant traits in the electronic health record (EHR). Outcomes occurring within 1-year of RoR were ascertained by EHR review. Analyses were stratified by tier 1 and non–tier 1 disorders.


Actionable findings were present in 122 individuals and results were disclosed to 98. The average penetrance for tier 1 disorder variants (67%; n = 58 individuals) was higher than in non–tier 1 variants (46.5%; n = 58 individuals). After excluding 45 individuals (decedents, nonresponders, known genetic diagnoses, mosaicism), ≥1 outcomes were noted in 83% of 77 participants following RoR; 78% had a process outcome (referral to a specialist, new testing, surveillance initiated); 68% had an intermediate outcome (new test finding or diagnosis); 19% had a clinical outcome (therapy modified, risk reduction surgery). Risk reduction surgery occurred more often in participants with tier 1 than those with non–tier 1 variants.


Relevant phenotypic traits were observed in 57% whereas a clinical outcome occurred in 19% of participants with actionable genomic variants in the year following RoR.

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Fig. 1: Participant selection for penetrance and outcomes analyses.

Data availability

Data is deposited in dbGaP (accession code phs001616.v2.p2) at website


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The RAVE study was funded as part of the NHGRI-supported eMERGE (Electronic Records and Genomics) Network (U01HG006379) and by the Mayo Center for Individualized Medicine. I.J.K. was additionally funded by K24 HL137010.

Author information




Conceptualization: I.J.K., R.S., N.L. Data curation: D.K., O.E., C.L. Formal analysis: O.E. Funding acquisition: I.J.K. Investigation: O.E., C.L., F.F., L.A. Resources: I.J.K. Supervision; I.J.K. Visualization: O.E. Writing—original draft: I.J.K., O.E., C.L. Writing—review & editing: I.J.K., O.E., C.L.

Corresponding author

Correspondence to Iftikhar J. Kullo.

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Ethics Declaration

RAVE study candidates were asked to complete a study consent form and health questionnaires, and provide a blood sample (if an existing sample was not available) to participate in this study. This study and the informed consent process were approved by the Mayo Institutional Review Board. Information about the Mayo Clinic Biobank’s collection and enrollment methods are described here:

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The authors declare no competing interests.

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Lee, C., Elsekaily, O., Kochan, D.C. et al. Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing. Genet Med (2021).

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