Saturation genome editing-based clinical classification of BRCA2 variants

Sounak Sahu, Melissa Galloux, Eileen Southon, Dylan Caylor, Teresa Sullivan, Matteo Arnaudi, Maria Zanti, Josephine Geh, Raj Chari, Kyriaki Michailidou, Elena Papaleo and Shyam K. Sharan ()
Additional contact information
Sounak Sahu: National Cancer Institute
Melissa Galloux: Independent bioinformatician
Eileen Southon: National Cancer Institute
Dylan Caylor: National Cancer Institute
Teresa Sullivan: National Cancer Institute
Matteo Arnaudi: Technical University of Denmark
Maria Zanti: The Cyprus Institute of Neurology and Genetics
Josephine Geh: National Cancer Institute
Raj Chari: Frederick National Laboratory for Cancer Research
Kyriaki Michailidou: The Cyprus Institute of Neurology and Genetics
Elena Papaleo: Technical University of Denmark
Shyam K. Sharan: National Cancer Institute

Nature, 2025, vol. 638, issue 8050, 538-545

Abstract: Abstract Sequencing-based genetic tests have uncovered a vast array of BRCA2 sequence variants1. Owing to limited clinical, familial and epidemiological data, thousands of variants are considered to be variants of uncertain significance2–4 (VUS). Here we have utilized CRISPR–Cas9-based saturation genome editing in a humanized mouse embryonic stem cell line to determine the functional effect of VUS. We have categorized nearly all possible single nucleotide variants (SNVs) in the region that encodes the carboxylate-terminal DNA-binding domain of BRCA2. We have generated function scores for 6,551 SNVs, covering 96.4% of possible SNVs in exons 15–26 spanning BRCA2 residues 2479–3216. These variants include 1,282 SNVs that are categorized as missense VUS in the clinical variant database ClinVar, with 77.2% of these classified as benign and 20.4% classified as pathogenic using our functional score. Our assay provides evidence that 3,384 of the SNVs in the region are benign and 776 are pathogenic. Our classification aligns closely with pathogenicity data from ClinVar, orthogonal functional assays and computational meta predictors. We have integrated our embryonic stem cell-based BRCA2-saturation genome editing dataset with other available evidence and utilized the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for clinical classification of all possible SNVs. This classification is available as a sequence–function map and serves as a valuable resource for interpreting unidentified variants in the population and for physicians and genetic counsellors to assess BRCA2 VUS in patients.

Date: 2025
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DOI: 10.1038/s41586-024-08349-1

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