BRCA2 – Sarcoma

Recent multi-cohort analyses have identified BRCA2 germline variants in sarcoma predisposition. In an international 2016 study, BRCA2 was one of several DNA repair genes contributing to sarcoma risk (PMID:27554610). Targeted sequencing of 66 young Asian patients revealed pathogenic BRCA2 variants in at least one patient among the nine carriers of GPVs (13.6%) (PMID:28878254). Family-based screening of 23 breast-sarcoma pedigrees detected BRCA2 mutations in three unrelated families (13%) (PMID:17224268), including the c.8878C>T (p.Gln2960Ter) allele. More recently, a 2023 panel of 177 pediatric and young adult sarcoma cases classified BRCA2 as an emerging risk gene among 21.5% with GPVs (PMID:37536918). Collectively, four probands have BRCA2 variants with no segregation data or sarcoma-specific functional validation, supporting a Limited ClinGen classification.

BRCA2 predisposition to sarcoma follows an autosomal dominant inheritance. Although BRCA2’s tumor suppressor role via homologous recombination and RAD51 interaction is well-established, sarcoma-specific in vitro or in vivo functional studies are lacking (PMID:11923292). Genetic testing of BRCA2 may be considered in young sarcoma patients, but evidence for routine clinical screening remains limited.

References

• Cancer discovery • 2016 • Unfurling the Genetic Map of Sarcomas PMID:27554610
• Scientific reports • 2017 • Germline Mutations in Cancer Predisposition Genes are Frequent in Sporadic Sarcomas PMID:28878254
• European journal of cancer • 2007 • Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families PMID:17224268
• Journal of medical genetics • 2023 • Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes PMID:37536918

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