Fig. 3: Genomic mapping of the case-control analysis for BRCA2.

Overlay of the case-control likelihood ratios (LRs) and the logistic regression odds ratio (OR) estimates is represented within each exon (middle panel). Exons are sequentially numbered from 1 to 27 and annotated from left to right to match the MANE Select transcripts. Case-control LRs (top panel) are represented on a continuous log2-transformed y axis with axis breaks. For the case-control LR analysis, the red color gradient represents LR reaching suggested ACMG/AMP evidence in favor of pathogenicity with strength levels ranging from very strong (dark red) to supporting (yellow). The green color gradient represents LR reaching ACMG/AMP evidence against pathogenicity with strength levels ranging from very strong (dark green) to supporting (light green). Variants with an LR of “No evidence” are not plotted. For the logistic regression analysis (bottom panel), orange color represents OR estimates reaching the strong PS4 criterion (OR ≥ 4.0, P value < 0.05, and confidence interval (CI) not including 2.0). Variants with OR estimates not reaching the PS4 criterion are not plotted. Associations were adjusted for age and study country (BCAC dataset), age and ethnic group (CARRIERS dataset), and age and genetic ancestry (UKB dataset). Only variants present in both cases and controls were analyzed. ORs with 95% CIs were estimated for each dataset and combined using a fixed-effects, inverse-variance meta-analysis in the ‘metafor’ R package to derive an overall test of association. A two-sided likelihood ratio test (LRT) was used to calculate P-values. No adjustments were made for multiple comparisons. For visualization purposes, the y-axis for logistic regression is represented in reverse order. LCI, lower confidence interval. Sequence ontology variant consequence (“Consequence”) is represented with different symbols.