Amanda Spurdle

Evaluation of variants in known or candidate high-risk cancer genes

Background: Panel gene testing is increasingly applied to identify the underlying genetic cause of cancer in patients with suspected hereditary cancer. Identification of a pathogenic variant directly influences clinical management for patients and their at-risk relatives, setting the path for preventative and increasingly chemotherapeutic options. Unfortunately, such testing often identifies variants with uncertain impact on function and clinical phenotype. Such variants of uncertain clinical significance create considerable difficulties for counselling and clinical management. A range of methods can be useful for assessing variants, including bioinformatic analysis, assays of mRNA and protein function, and also investigating association with clinical features such as segregation in families, age at onset /phenotype in case-control studies and tumour pathology.

Aim: To use statistical and laboratory methods to assess the clinical relevance of rare cancer gene sequence variants identified by clinical genetic testing of patients with suspected hereditary cancer, identified in Australia or through the international consortia such as ENIGMA.

Approach: This project will assess the effect of variants on gene/protein function using a variety of bioinformatic predictions, molecular biological assays and/or statistical analyses. Techniques may include RNA analyses using LCLs and/or constructs, protein assays in collaboration with other laboratories, pedigree analysis and simple statistical analyses of clinical factors predictive of pathogenic variant status, to develop calibrated measures of association with disease for use in multifactorial likelihood analysis.

Outcome: Analysis of specific variants will provide evidence regarding their pathogenicity for translation in the clinical setting. Comparison of assay results with risk will form the foundation for improving bioinformatic prediction tools and incorporating predictions and/or biological assay results in statistical models of risk prediction.