PROJECT SUMMARY/ABSTRACT In this supplement, we propose two distinct activities focused on the use of genomics in population screening. We will establish a new ClinGen working group to develop an evidence framework to inform decision-making about which targets to include in population screening efforts in unselected populations. We will leverage the expertise and well-established procedures of the ClinGen Actionability Working Group, including recent efforts to develop a new framework for the polygenic risk score (PRS) context. Given that nascent population genomic screening efforts are already in underway in some centers and health systems, this framework development is timely and necessary to provide guidance on conditions that should be considered for screening based on key factors including actionability and cost effectiveness. Overall, this work will significantly contribute to the advancement of genomic medicine at the population scale and provide evidence-based assessments of population health impact for a broad range of end-users. This supplement also requests funds for the UNC team to host and oversee the 2023 annual meeting of the NHGRI Division of Genomic Medicine meeting (GM XV), planned and conducted by the Advisory Council’s Genomic Medicine Working Group. These meetings have historically addressed timely topics in genomic medicine to identify research directions for the field and for NHGRI. The focus of the 2023 meeting will be on genomics and population screening, with meeting objectives aligned with assessing the current state of the science, determining the key challenges and opportunities, and outlining a research agenda. The UNC ClinGen grant is well- suited to help plan this meeting given our close relationship and subcontract with the American College of Medical Genetics and Genomics (ACMG), through which we have coordinated dozens of in-person, virtual, and hybrid Steering Committee meetings and in-person meetings between members of ClinGen’s Clinical Domain Working Groups and Expert Panels.

SUMMARY AND CONNECTION TO CLINGEN (PROJECT NARRATIVE) Population screening for monogenic disease risk is increasingly being used among unselected individuals in hopes of improving ascertainment and health outcomes. There is a critical need for a framework to guide decision making about which genes and conditions are appropriate for population screening. In part, this decision will hinge on metrics of “actionability” (meaning that interventions are available that can reduce morbidity/mortality or ameliorate the poor health outcomes associated with the condition). However, there are many additional factors that must be considered for population-level genomic screening, including economic evaluations and ethical/legal/social implications. In this supplement, we propose to leverage the established procedures of the ClinGen Actionability Work Group to develop a framework to guide decision- making on which genetic findings to return to individuals in population-level screening efforts, thereby contributing to the advancement of genomic medicine at the population scale. This new working group will represent an expansion of ClinGen’s contribution to evidence-based genomic medicine. Additionally, UNC was asked by the NHGRI leadership to request supplemental funds to cover the planning and execution of the Genomic Medicine XV Meeting, sponsored by the NHGRI and hosted in-person in the Washington DC area November 8-9, 2023.