| Summary: | Germline pathogenic variants in <i>BRCA1</i> and <i>BRCA2</i> increase cumulative lifetime risk up to 75% for breast cancer and 76% for ovarian cancer. Genetic testing for <i>BRCA1</i> and <i>BRCA2</i> pathogenic variants has become an important part of clinical practice for cancer risk assessment and for reducing individual risk of developing cancer. Genetic testing can produce three outcomes: positive (a pathogenic variant), uninformative (no pathogenic variant) and uncertain significance (a variant of unknown clinical significance). More than one third of <i>BRCA1</i> and <i>BRCA2</i> variants identified have been classified as variants of uncertain significance, presenting a challenge for clinicians. To address this important clinical challenge, a number of studies have been undertaken to establish a gene expression phenotype for pathogenic <i>BRCA1</i> and <i>BRCA2</i> variant carriers in several diseased and normal tissues. However, the consistency of gene expression phenotypes described in studies has been poor. To determine if gene expression analysis has been a successful approach for variant classification, we describe the design and comparability of 23 published gene expression studies that have profiled cells from <i>BRCA1</i> and <i>BRCA2</i> pathogenic variant carriers. We show the impact of advancements in expression-based technologies, the importance of developing larger study cohorts and the necessity to better understand variables affecting gene expression profiles across different tissue types.
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