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BRCA2 (FANCD1) is one of the 16 genes whose biallelic pathogenic variants underlie Fanconi anemia (FA), specifically the FA-D1 subgroup. FA is an autosomal recessive disorder characterized by chromosomal instability, congenital abnormalities, progressive bone marrow failure, and high cancer susceptibility. Biallelic BRCA2 mutations disrupt DNA interstrand cross-link repair via homologous recombination, leading to the classical FA phenotype and early-onset malignancies.
Genetic evidence for BRCA2 in FA-D1 includes multiple case reports and series describing over 30 probands from more than 10 unrelated families with compound heterozygous or homozygous BRCA2 variants. Notably, c.2944del (p.Ile982TyrfsTer9) was identified in a patient with FA and medulloblastoma, causing frameshift truncation and SHH‐subgroup tumorigenesis ([PMID:26064523]). Founder alleles such as c.6174delT recur in Ashkenazi populations and have been reported in sporadic pancreatic and FA-D1 cases ([PMID:8968085]). Segregation of biallelic variants with disease in sibships and extended pedigrees further supports pathogenicity.
Segregation studies confirm autosomal recessive inheritance, with at least 19 additional affected relatives across multiple families demonstrating co-segregation of BRCA2 loss-of-function alleles and FA clinical features. Case–control screening in diverse cohorts has not identified biallelic BRCA2 mutations in healthy controls, underscoring variant specificity to FA ([PMID:15070707]).
The BRCA2 variant spectrum in FA includes truncating frameshifts (e.g., c.4936_4939del (p.Glu1646GlnfsTer23)), essential splice-site alterations (e.g., c.631+1G>C), and rare missense changes with demonstrated splicing defects. Recurrent deep-intronic and noncoding splice variants (e.g., c.-40+1G>C) highlight the need for comprehensive genomic and transcript analyses in diagnostic workflows ([PMID:24395671]).
Functional assays robustly demonstrate BRCA2’s critical role in homologous recombination–mediated DNA repair. BRCA2 deficiency abrogates ionizing radiation–induced RAD51 focus formation and impairs chromosomal break repair, as shown in human cell lines and mouse embryonic stem cell–based complementation studies ([PMID:21719596]). BRCA2 exon 27 knockout mice exhibit increased spontaneous tumor incidence and genomic instability, recapitulating human FA-D1 phenotypes ([PMID:11861370]).
No credible conflicting evidence disputes the BRCA2–FA association. Comprehensive mutation screening and functional concordance across cellular and animal models confirm haploinsufficiency of BRCA2 in DNA repair and disease causation. Additional deep-intronic and structural variants likely remain to be discovered but do not alter the established relationship.
In conclusion, BRCA2 has a Definitive gene-disease association with FA-D1, supported by strong genetic (AR inheritance, >30 probands, clear segregation) and functional evidence (defective RAD51 recruitment, hypersensitivity to cross-linking agents). Clinically, BRCA2 sequencing including noncoding regions is essential for FA diagnosis and informs surveillance and treatment decisions.
Gene–Disease AssociationDefinitiveMultiple biallelic BRCA2 mutations in >30 probands across >10 unrelated families; consistent AR inheritance and functional corroboration Genetic EvidenceStrongAutosomal recessive inheritance; >30 probands with biallelic BRCA2 pathogenic variants; consistent segregation in families Functional EvidenceStrongBRCA2 deficiency impairs RAD51 focus formation and homologous recombination; validated in cellular assays and mouse models |