Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identifed in Clinical Genetic Testing
Journal Title: Sultan Qaboos University Medical Journal - Year 2015, Vol 15, Issue 2
Abstract
Objectives: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. Tis study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. Methods: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub) for BRCA gene analysis. Te analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. Results: In most of the variants, the analysis showed different in silico interpretations. Tis illustrates the interpretation challenges faced by diagnostic laboratories. Conclusion: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is signifcant discordance in the classifcation of some missense variants in the BRCA genes. Tis discordance leads to complexities in interpreting and reporting these variants in a clinical context. Te authors have developed a simple procedure for analysing variants; however, those of unknown signifcance largely remain unknown. As a consequence, the clinical value of some reports may be negligible.
Authors and Affiliations
Clare Brookes| Department of Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand, Stella Lai| Department of Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand, Elaine Doherty| Department of Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand, Donald R. Love| Department of Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand
Keywords
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