# Identification and Computational Analysis of BRCA2 Variants in Mexican Women from Jalisco, Mexico, with Breast and Ovarian Cancer

## TL;DR

This study identifies BRCA2 gene variants in Mexican women with breast and ovarian cancer, highlighting their potential impact on cancer risk and response to treatment.

## Contribution

The study reports six BRCA2 variants of uncertain significance not previously reported in other populations and emphasizes the need for population-specific genetic panels in Mexico.

## Key findings

- BRCA2 variants were found in 12.86% of patients, with a higher frequency in ovarian cancer cases.
- Several variants were located in key functional domains and predicted to be deleterious.
- BRCA2-positive breast cancer patients were younger at diagnosis and showed a trend toward lower complete response.

## Abstract

Background: Breast and ovarian cancers (BC and OC) are prevalent malignancies in women globally, with germline variants in the BRCA2 gene significantly increasing the risk of developing these cancers. Despite extensive studies, the frequency and impact of BRCA2 variants in women from Jalisco, Mexico, remain underexplored. Objective: The aim of this study was to identify and characterize BRCA2 gene variants in Mexican women diagnosed with BC and OC and to assess their functional and structural consequences using computational analyses. Methodology: Genomic DNA from 140 Mexican women with BC and/or OC, selected based on clinical criteria suggestive of BRCA2 variants, was sequenced using NGS targeting BRCA2 coding regions. Functional effects were predicted with Ensembl VEP, SIFT, and PolyPhen-2. Structural impacts of missense variants were assessed using HOPE and AlphaFold models. Results: BRCA2 variants were identified in 12.86% of patients, with higher frequency in OC (21.05%) than BC (12%). Several mapped to key functional domains, including BRC repeats and the DNA-binding domain. Many were predicted as deleterious or probably damaging, though clinical classifications were often conflicting. Structural analysis indicated potential disruptions in protein stability or interactions for most missense variants. Clinically, BRCA2-positive BC patients were younger at diagnosis and showed a trend toward lower complete response. Conclusion: BRCA2 variants were found in 12.86% of patients, including six VUSs not reported in other populations. Several affected key functional domains with predicted deleterious effects. Findings support the need for genetic panels tailored to the Mexican population.