# Germline BRCA1/2 Variants in Polish Patients with Family History of Breast and Ovarian Cancer: Prevalence, CNV Detection, and Identification of a Novel Loss-of-Function Mutation

## TL;DR

The study examines BRCA1/2 gene variants in Polish individuals with a family history of breast and ovarian cancer, identifying a new mutation and highlighting challenges in genetic diagnosis.

## Contribution

A novel loss-of-function mutation in the BRCA1 gene and a deletion in exon 21 were identified in Polish patients.

## Key findings

- 16 unique pathogenic or likely pathogenic BRCA1/2 variants were identified in 22 patients.
- A deletion in exon 21 of the BRCA1 gene was found in two patients.
- Only 4.89% of the cohort had detectable genetic predisposition to cancer.

## Abstract

Among the Polish population, around 4% of breast cancer patients and 10% of ovarian cancer patients have pathogenic variants of the BRCA1 gene, whereas variants of the BRCA2 gene are uncommon. Short-read sequencing provides a comprehensive range of data, including the detection of CNVs (copy number variants), but it still poses challenges when using standard NGS workflows. In this study, we investigated genetic variants in a cohort of 450 unaffected individuals with a family history of breast and/or ovarian cancer, involving at least one first-degree relative, with particular emphasis on CNV detection. In our study, the detection accuracy was just 4.89%, indicating that the genetic predisposition to cancer could not be demonstrated in the majority of patients.

Background/Objectives: Pathogenic and likely pathogenic variants in the BRCA1 and BRCA2 genes are associated with a significantly increased risk of breast and/or ovarian cancer. We investigated genetic variants in a cohort of 450 unaffected individuals with a family history of breast and/or ovarian cancer, involving at least one first-degree relative. Methods: Next-generation sequencing (NGS) was used to analyze the coding regions of these two genes, with copy number variation (CNV) analysis. Results: A total of 16 unique to our cohort variants classified as pathogenic or likely pathogenic were identified in 22 patients, including one novel loss-of-function variant in BRCA1 gene. Furthermore, we identified a deletion of exon 21 in the BRCA1 gene in two patients. Conclusions: These results emphasize the difficulties involved in molecular diagnostics and indicate the need for further research into new predictive models for patients with hereditary breast and ovarian cancer.