BRCA2 – Medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumor and arises sporadically or within cancer‐predisposition syndromes. Germline variants in BRCA2 (FANCD1) confer Fanconi anemia (FA) when biallelic and have been implicated in medulloblastoma development through loss of homologous recombination repair.

Clinical Validity

Autosomal recessive inheritance of medulloblastoma predisposition due to BRCA2 is supported by biallelic pathogenic variants in 11 unrelated FA patients (PMID:19530235), two affected siblings within one kindred (PMID:19530235), and an international cohort of eight patients with biallelic BRCA2 variants and SHH‐subgroup medulloblastoma (PMID:38685107). One report describes a homozygous missense variant in a 13-year-old boy with medulloblastoma (PMID:22044372). Overall, 21 probands meet criteria for a moderate association.

Genetic Evidence

Inheritance mode: Autosomal recessive. Segregation: two affected siblings with concordant biallelic variants (PMID:19530235). Case series include 11 FA/D1 patients and an eight‐patient cohort. Variant spectrum is dominated by loss-of-function alleles (frameshift, splice, nonsense); representative variant: c.5946del (p.Ser1982Ter) (PMID:19530235). A heterozygous 6174delT (p.Phe2058LeufsTer12) case without FA also presented with disseminated medulloblastoma (PMID:26380221).

Functional Evidence

BRCA2 deficiency disrupts DNA interstrand crosslink repair and homologous recombination, as demonstrated by hypersensitivity to DNA‐damaging agents and genomic instability in cell and animal models. Loss of BRCA2 function recapitulates FA phenotypes and supports a tumor‐promoting mechanism via impaired genome maintenance.

Conflicting Evidence

No studies have refuted the biallelic association; isolated heterozygous events warrant further population studies.

Integration & Conclusion

Biallelic pathogenic BRCA2 variants underlie a recessive form of Fanconi anemia that predisposes to medulloblastoma, particularly of the SHH molecular subgroup, with early onset and poor prognosis. Current evidence reaches a moderate level by ClinGen standards, supporting the inclusion of BRCA2 in genetic testing panels for pediatric medulloblastoma, especially in FA‐suspected cases.

Key Take-home: Screening for BRCA2 pathogenic variants is clinically valuable for early diagnosis and family counseling in medulloblastoma associated with Fanconi anemia.

References

• Pediatric blood & cancer • 2009 • Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor. PMID:19530235
• Journal of neurosurgery. Pediatrics • 2011 • Variation in the BRCA2 gene in a child with medulloblastoma and a family history of breast cancer. PMID:22044372
• Frontiers in oncology • 2015 • Disseminated Medulloblastoma in a Child with Germline BRCA2 6174delT Mutation and without Fanconi Anemia. PMID:26380221
• Adenine AI • 2025 • International cohort of Fanconi anemia patients with biallelic BRCA2 variants and medulloblastoma. PMID:38685107

Evidence Based Scoring (AI generated)