Integrating enriched case data from national laboratory testing with population-based case-control analyses: a novel statistical likelihood-ratio methodology for PS4 applied to 325,345 breast cancer cases and 671,006 controls

Background: For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods: Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected,