# Unraveling the Role of BRCA1 variants in Dysregulation of Transcriptional and Post-Transcriptional Mechanisms in Breast Cancer

## TL;DR

This study identifies and analyzes BRCA1 gene variants in breast cancer patients to understand their role in disease development.

## Contribution

The study reports two novel BRCA1 missense variants and their predicted effects on protein interactions and mRNA stability.

## Key findings

- Two novel BRCA1 variants were found to disrupt interactions with PALB2 and importin alpha’s NLS2 site.
- One variant was predicted to cause loss of hsa-miR-1179 binding site, affecting mRNA regulation.
- Four variants were predicted to alter mRNA structure and stability, potentially contributing to oncogenesis.

## Abstract

To screen BRCA1 gene variants and predict potential role of the identified variants in breast cancer.

This case-control study included two hundred and fifty breast cancer patients and equal healthy individuals from the Federal Breast Cancer Screening Centre, Pakistan Institute of Medical Sciences, Islamabad from March 2021- January 2023. Demographic data was collected through questionnaires and clinical data was assessed using mammograms, ultrasound, histopathology and immunohistochemistry reports. Polymerase chain reaction and Sanger sequencing approach were used to detect variants in BRCA1 gene. In-silico analyses were carried out to predict mutation effect, miRNA binding site alterations and change in mRNA structure and stability.

Invasive ductal carcinoma was the most prevalent type of breast cancer. Old age [OR: 2.8149 (1.5995 to 4.9538) p value = 0.0003] and family history [OR: 4.3186 (1.7336 to 10.7581) p value = 0.001] were significant breast cancer risk. Six variants were identified. Two novel missense variants, Chr17:43082553A>T and Chr17:43093710A>T were predicted deleterious as these disrupted interaction with PALB2 and importin alpha’s NLS2 site, respectively. In silico analysis predicted the loss of hsa-miR-1179 binding site due to variant Chr17:43093220T>C. Moreover, four variants were predicted to affect the mRNA structure and stability.

Two novel variants were predicted to be pathogenic. In-silico analysis predicted the loss of miRNA binding site along with change in mRNA secondary structure plus stability, possible mechanisms for oncogenesis. Further, expressional studies are required to confirm BRCA1 gene dysregulation in breast cancer due to these variants.