Association between type and location of germline BRCA1/2 pathogenic or likely pathogenic variants with phenotype and prognosis in young patients with breast cancer

BRCA1, BRCA2 (variant types and exonic location)

International BRCA BCY cohort (3,294 patients, 109 centers, 5 continents): analysis of the impact of variant type (truncating vs missense) and exonic location on overall survival (OS) and disease-free survival (DFS)

The BRCA BCY cohort (Breast Cancer in Young patients — breast cancer in patients ≤40 years) (3,294 BRCA1/2 carrier patients, ≤40 years, 2000–2020, 109 centers, 5 continents) documents new prognostic granularity according to variant type and location. For BRCA1, truncating variants are associated with significantly worse overall survival than non-truncating variants (HR 2.00, CI 1.17–3.41). For BRCA2, variants in exons 15–26 are associated with shorter disease-free survival compared to exon 10 variants. These data introduce a genotype-phenotype dimension into genetic counseling.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

First major signal suggesting that not all BRCA1/2 pathogenic variants should be treated identically in the discussion of contralateral prophylactic mastectomy. These results require prospective confirmation before guideline modification, but provide a discussion basis for BRCA1 truncating patients with a more severe profile.

international cohort n=3,294 +2; direct clinical impact (prognostic stratification) +2; genotype-phenotype novelty +2; Ann Oncol +1; 5 continents +1