Germline pathogenic variants in BRCA1
increase cumulative lifetime risk up to 75% for breast cancer and 76% for ovarian cancer. Genetic testing for BRCA1
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 BRCA1
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 BRCA1
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 BRCA1
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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