Medical sciences (Basel, Switzerland) · 2026
Identification and Computational Analysis of BRCA1 Variants in Mexican Women from Jalisco, Mexico, with Breast and Ovarian Cancer.
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Gallegos-Arreola Martha Patricia, Garibaldi-Ríos Asbiel Felipe, Dávalos-Rodríguez Ingrid Patricia, Magaña-Torres María Teresa, Figuera Luis E, Zúñiga-González Guillermo Moisés, Gómez-Meda Belinda Claudia, Torres-Mendoza Blanca Miriam, Villegas-Pacheco Raquel, Gómez-Cerda René, Cárdenas-Valdez Julio César, Meza-Chavolla Sergio Osvaldo, Rosales-Reynoso Mónica Alejandra, Ángeles-Bueno Wenceslao Guillermo, Gómez-Villegas María José, Espinoza Daniela Del Rocío Panduro, García-Ortiz José Elías
Аннотация
BACKGROUND: Breast and ovarian cancer are among the most common neoplasms in women, and germline variants in the BRCA1 gene markedly increase the risk of developing them. Despite existing studies, the frequency and spectrum of BRCA1 variants in women from Jalisco, Mexico, remain underexplored.
OBJECTIVE: To identify and characterize BRCA1 variants in a cohort of Mexican women with breast and ovarian cancer, and to assess their functional and splicing consequences through computational analysis.
METHODOLOGY: Genomic DNA from 228 women with breast and/or ovarian cancer, selected by clinical criteria suggestive of hereditary cancer, was analyzed by next-generation sequencing. The functional impact of point variants was predicted with Ensembl VEP, SIFT, PolyPhen-2, REVEL, CADD, and AlphaMissense, and their effect on splicing was evaluated with SpliceAI, using the MANE Select canonical transcript (NM_007294.4).
RESULTS: BRCA1 variants were identified in 14.0% of this screening-enriched cohort, with carrier proportions of 16.2% in ovarian and 13.6% in breast cancer; these figures reflect a selected series and do not represent population prevalence. Breast cancer carriers showed a younger age at diagnosis, a higher proportion of the triple-negative phenotype, and a stronger family history. Fourteen-point variants and four large rearrangements were detected, with a predominance of truncating loss-of-function alterations. The recurrent missense variant c.5123C>A (p.Ala1708Glu), located in the BRCT1 domain, was the most relevant finding, present in 28.1% of carriers (9/32). The computational analysis did not reclassify variants on its own but provided complementary evidence (PP3/BP4) consistent with current classifications: it allowed reannotation of c.5243G>A from nonsense to missense, supported the pathogenic nature of the intronic splice variant c.4987-3C>A, and was concordant with the likely benign interpretation of c.2735A>G, while c.3367G>T remained of uncertain significance.
CONCLUSIONS: This cohort from Western Mexico harbors a distinctive spectrum of BRCA1 variants, including the recurrent c.5123C>A variant, which may reflect a regional founder effect warranting haplotype analysis. These findings underscore the need for local evidence and for genetic panels adapted to the Mexican population, to enable accurate and equitable variant interpretation and access to targeted therapies such as PARP inhibitors.
OBJECTIVE: To identify and characterize BRCA1 variants in a cohort of Mexican women with breast and ovarian cancer, and to assess their functional and splicing consequences through computational analysis.
METHODOLOGY: Genomic DNA from 228 women with breast and/or ovarian cancer, selected by clinical criteria suggestive of hereditary cancer, was analyzed by next-generation sequencing. The functional impact of point variants was predicted with Ensembl VEP, SIFT, PolyPhen-2, REVEL, CADD, and AlphaMissense, and their effect on splicing was evaluated with SpliceAI, using the MANE Select canonical transcript (NM_007294.4).
RESULTS: BRCA1 variants were identified in 14.0% of this screening-enriched cohort, with carrier proportions of 16.2% in ovarian and 13.6% in breast cancer; these figures reflect a selected series and do not represent population prevalence. Breast cancer carriers showed a younger age at diagnosis, a higher proportion of the triple-negative phenotype, and a stronger family history. Fourteen-point variants and four large rearrangements were detected, with a predominance of truncating loss-of-function alterations. The recurrent missense variant c.5123C>A (p.Ala1708Glu), located in the BRCT1 domain, was the most relevant finding, present in 28.1% of carriers (9/32). The computational analysis did not reclassify variants on its own but provided complementary evidence (PP3/BP4) consistent with current classifications: it allowed reannotation of c.5243G>A from nonsense to missense, supported the pathogenic nature of the intronic splice variant c.4987-3C>A, and was concordant with the likely benign interpretation of c.2735A>G, while c.3367G>T remained of uncertain significance.
CONCLUSIONS: This cohort from Western Mexico harbors a distinctive spectrum of BRCA1 variants, including the recurrent c.5123C>A variant, which may reflect a regional founder effect warranting haplotype analysis. These findings underscore the need for local evidence and for genetic panels adapted to the Mexican population, to enable accurate and equitable variant interpretation and access to targeted therapies such as PARP inhibitors.