# Classification of Gene Variants in a Danish Population with Suspected Predisposition to Hereditary Breast and/or Ovarian Cancer

## TL;DR

This study analyzed gene variants in Danish patients suspected of hereditary breast and ovarian cancer to better classify variants of unknown significance.

## Contribution

The study reclassified 22.8% of variants of unknown significance using association and splice analysis in a Danish population.

## Key findings

- 10.6% of patients carried likely pathogenic or pathogenic variants, mostly in BRCA1 and BRCA2.
- 27.1% of patients carried variants of unknown significance, primarily in BARD1 and ATM.
- 22.8% of previously classified VUSs were reclassified using updated guidelines and additional analyses.

## Abstract

This study aimed to classify and investigate the distribution of gene variants in 13 clinically relevant genes of 5923 Danish patients with suspected hereditary predisposition to breast and/or ovarian cancer, all of whom were tested with the same gene panel. The growth in genetic analysis over the last 25 years has generated an increasing number of variants of unknown significance (VUSs). These present challenges for daily clinical counselling and decision-making about whether a carrier should be offered inclusion in a surveillance program or risk-reducing surgery. We examined VUSs using two methods: an association analysis comparing the case group to a Swedish control group, and splice analysis using RNA sequencing.

Background: Gene variants of unknown significance (VUSs) present a challenge in genetic counselling. The primary aim of this study was to describe the spectrum of genetic findings in a cohort of 5923 Danish patients with suspected predisposition to hereditary breast and/or ovarian cancer, with a focus on classifying gene variants and investigating their distribution. Methods: The gene variants were classified using the American College of Medical Genetics (ACMG) guidelines as well as gene-specific guidelines where applicable. The identified VUSs were further examined through association analysis, comparison of the frequencies in this Danish population to those in the Swedish population using gnomAD 2.1, and splice analysis using RNA sequencing. Results: Of 167 variants that were clinically classified as VUSs prior to this research study, 38 (22.8%) were either up- or downgraded based on the guidelines that were used. We found that 630 patients (10.6%) carried a likely pathogenic or pathogenic variant, mainly in BRCA1 (31.9%) and BRCA2 (26.0%). VUSs were carried by 1606 (27.1%) patients, mainly in BARD1 (27.6%) and ATM (19.3%). Our association study assigned criteria for 10 gene variants, while our splice analysis assigned criteria for 3 gene variants but did not reclassify the variants. Conclusions: A total of 22.8% of the 167 variants that were observed in this study and which were previously classified as VUSs in a clinical setting were reclassified in this study. In total, 10.6% of the patients with a suspected predisposition to hereditary breast and/or ovarian cancer carried a likely pathogenic or pathogenic variant. The high incidence of VUSs observed in this study reflects the challenges faced in the daily clinical setting.