Background: Empirical observations at Familial Cancer Centres across Australia have identified many families with unusual clusters of cancers and/or individuals with multiple primary cancers. Although such cases are strong candidates for the presence of a hereditary cancer syndrome, in most instances conventional phenotype directed genetic testing does not identify a plausible disease-causing variant. We present the latest findings from an ongoing project conducted by Australian Genomics and the Inherited Cancer Connect (ICCon) partnership that focuses on individuals with these unusual cancer presentations, and assess whether the adoption of WGS into routine clinical practice is feasible.
Methods: We prioritized candidate germline variants (single-nucleotide, copy-number and structural) in a subset of > 100 genes, considered clinically actionable within the context of hereditary cancer. Variants were classified using ACMG/AMP guidelines and reviewed by a multidisciplinary team panel.
Results: As of August 2020, our cohort consists of 173 individuals. Phenotype-matched (likely) causal variants were identified in several cases, including the identification of candidate APC promoter variants missed by prior APC testing in two polyposis affected families. Similarly, pathogenic BRCA2 variants were detected in participants who did not meet the standard clinical criteria to warrant single gene BRCA2 testing. Participants were also found to be carriers of previously unidentified gene alterations implicated in hereditary cancer syndromes.
Conclusions: We have demonstrated that the use of WGS in cases of suspected hereditary cancer can lead to the identification of germline variants that are either not clinically indicated or detected by traditional phenotype-directed testing.