Saturation genome editing of BRCA1 across cell types improves interpretation of variant pathogenicity.

Saturation genome editing of BRCA1 in HAP1 cells scored 4,113 variants, achieving near-perfect discrimination of known pathogenic versus benign variants by function.

• Why it matters: Many reported BRCA1 single-nucleotide variants still lack definitive clinical interpretation, and whether variant effects stay consistent across cell types is poorly understood.
• What they did: The study performed saturation genome editing in HAP1 cells and built a parallel assay in human mammary epithelial cells (HMECs) to compare variant effects across cell lines, drug treatments, and genetic backgrounds.
• The result: Of 538 variants affecting gene function, nearly half of HAP1 loss-of-function variants scored neutrally in HMECs; discordant variants were hypomorphic and linked to intermediate cancer risk.

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