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The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between  BRCA1  or  BRCA2  pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to  BRCA1  or  BRCA2  mutations ( BRCAX  cases). 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23  BRCA1  carriers, 22  BRCA2  carriers, and 27  BRCAX  individuals. A subset of 10  BRCAX  individuals carried rare  BRCA1/2  sequence variants considered to be of low clinical significance (LCS).  BRCA1  and  BRCA2  mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of  BRCAX  individuals formed a distinct cluster, but  BRCAX  individuals with LCS variants had expression profiles similar to  BRCA1/2  mutation carriers. Gaussian Process Classifier predicted  BRCA1 ,  BRCA2  and  BRCAX  status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of  BRCAX  samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for  BRCAX  samples without an LCS variant (82–94%), poor for  BRCAX  with an LCS (40–50%), and improved for pathogenic  BRCA1/2  mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71–100%). This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.

BRCA1 and BRCA2 Missense Variants of High and Low Clinical Significance Influence Lymphoblastoid Cell Line Post-Irradiation Gene Expression