Precision screening facilitates clinical classification of BRCA2-PALB2 binding variants with benign and pathogenic
Muthiah Bose1, Manika Indrajit Singh1, Morten Frödin2
1Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
The Journal of Clinical Investigation
|April 15, 2025
Summary
CRISPR-Select efficiently classified 49 of 54 BRCA2 variants of uncertain significance (VUS). This technology aids precision medicine by determining variant impact, improving patient care for cancer genetic screening.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Precision medicine relies on understanding genetic variant impact in cancer.
- Numerous BRCA1/BRCA2 variants of uncertain significance (VUS) lack classification due to insufficient data.
- This hinders accurate genetic screening for breast and ovarian cancer patients.
Purpose of the Study:
- To utilize CRISPR-Select technology for functional assessment of rare BRCA2 VUS.
- To determine the deleteriousness of VUS in the PALB2-binding domain of BRCA2.
- To improve the clinical classification of unclassified genetic variants.
Main Methods:
- Employed CRISPR-Select for endogenous locus assessment of 54 rare ClinVar VUS in BRCA2.
- Examined variant effects with and without PARPi, Cisplatin, or Mitomycin C.
- Integrated functional data with ClinGen expert panel recommendations for variant classification.
Main Results:
- Identified marked functional deficiency in variants within the exon 2-donor splice region and at Trp31.
- Observed intermediate phenotypes for T10K and G25R variants, indicating hypomorphic nature.
- Successfully classified 49 out of 54 VUS as likely benign (45) or likely pathogenic (4).
Conclusions:
- CRISPR-Select is a valuable tool for efficient clinical variant classification.
- This technology enhances the ability to interpret genetic variants.
- Future applications of CRISPR-Select will significantly improve patient care in precision oncology.
