What statement best describes the effect of polygenic risk on BRCA carriers?

• A. Polygenic risk can modulate risk in those with a pathogenic variant; the interaction is complex and an area of ongoing research.
• B. Polygenic risk completely determines cancer risk.
• C. Polygenic risk has no effect on risk in BRCA carriers.
• D. Polygenic risk always reduces risk in BRCA carriers.

Answer: (A)

Polygenic risk acts as a modifier of cancer risk in individuals who carry pathogenic BRCA variants. BRCA1/2 mutations raise baseline risk, but the exact likelihood for any given carrier varies because many common genetic variants each contribute a small effect. A high polygenic risk score can push a BRCA carrier’s lifetime risk higher, while a low score can lower it relative to other BRCA carriers, though their risk remains elevated compared to noncarriers. The way these variants combine—whether additively or multiplicatively—and how much they shift risk is still being studied, with results influenced by ancestry and study design. This is why polygenic risk is described as an area of ongoing research and a potential tool for refining personalized screening, rather than a definitive predictor.