Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta = 0.23 SDs; 95% CI, 0.18–0.29; p=2.6 × 10-19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR = 1.91; 95% CI, 1.52–2.40; p=2.7 × 10-8). The gene discussed is SAMHD1; the disease is breast cancer.