Clinical consequences of BRCA2 hypomorphism.

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• The tumor suppressor FANCD1/BRCA2 is vital for DNA homologous recombination repair (HRR).
• Biallelic BRCA2 pathogenic variants cause Fanconi anemia (FA), while monoallelic variants predispose to hereditary breast and ovarian cancer.
• Previously, a benign BRCA2 allele was assumed when co-occurring with a pathogenic variant.

Purpose of the Study:

• To investigate the functional impact of biallelic BRCA2 variants in a patient presenting with Fanconi anemia.
• To characterize the HRR activity of individual BRCA2 alleles in a patient's cells.
• To determine the threshold of HRR function required to prevent FA but not cancer predisposition.

Main Methods:

• Case study of a patient with biallelic BRCA2 variants (c.1813dup and c.7796A>G).
• Analysis of patient cell DNA damage response, including chromosome fragility, survival, cell cycle, and RAD51 foci.
• Development and application of a cell-based flow cytometric assay to measure single BRCA2 allele HRR contribution.

Main Results:

• Patient cells exhibited intermediate chromosome fragility, reduced survival, cell cycle defects, and decreased RAD51 foci after DNA damage.
• The missense BRCA2 allele partially restored HRR activity in a BRCA2 knockout cellular background.
• The hypomorphic BRCA2 allele retained 37-54% of normal HRR function.

Conclusions:

• A BRCA2 allele with 37-54% HRR function can prevent the clinical phenotype of Fanconi anemia.
• This level of residual HRR function does not prevent early-onset breast cancer or severe chemotherapy hypersensitivity.
• The study highlights the complex genotype-phenotype correlations in BRCA2-associated disorders.