Testing panels of hereditary cancer genes represents an important advance in medicine; however, the clinical impact of these tests is not yet fully understood. In this webinar, we will discuss a recent study on the clinical utility of panel testing in hereditary breast and ovarian cancer patients, presented at the American Society of Clinical Oncology meeting on June 1, 2015.
More than 1,000 BRCA1/BRCA2-negative individuals who met appropriate criteria for BRCA testing were studied. Of the 63 who carried non-BRCA mutations, the patient management implications of these findings were assessed under uniform criteria based on current practice guidelines. The study found that the majority of non-BRCA positive results would warrant consideration of a change in care for the patient, over and above any actions that would be considered based on personal and family history alone. Moreover, the study showed that genetic testing of family members would also be warranted given the management implications for relatives who tested positive for these non-BRCA genes.
These results show that panel testing can yield clinically relevant and actionable findings with potentially beneficial management impact for substantially more patients than BRCA1/BRCA2 testing alone can.
The study was conducted as a collaboration between Invitae, Massachusetts General Hospital, the Stanford Cancer Institute, and Beth Israel Deaconess Medical Center.
With increasing use of high-throughput sequencing and multi-gene panels for diagnostic purposes, there is growing concern about the potential for inconsistent variant classifications among clinical labs. The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) recently drafted new standards and guidelines for the interpretation of sequence variants (ISV) to address this concern. Draft versions of these guidelines were shared broadly with the clinical genetics community, feedback was incorporated, and an evidence-based checklist for interpreting Mendelian disease variants has now been published (Richards et al., Genet Med 2015). This checklist represents a major step toward evidence-assessment standardization and variant-classification consistency. However, many ISV criteria are quite expansive, which could result in inconsistency in their application. To date, a rigorous study has not been published examining the impact of these new guidelines on variant classification and clinical reporting. It also remains to be seen whether the new evidence checklist results in increased interpretation concordance between clinical laboratories. We considered these issues when validating our own laboratory’s classification procedures, which are based on the new ISV guidelines.
With the 2015 ACMG ISV guidelines as our guide, we developed Sherloc, a score-based classification system with detailed evidence criteria, inherent logic for handling interdependent evidence, and comprehensive notes outlining caveats, various use cases, and evidence considerations for each criteria. This system has been implemented in our clinical-testing workflow and refined over the past 20 months. To evaluate the concordance of Sherloc classifications with current community standards, we compared classifications of over 800 variants to a consensus classification derived from ClinVar submissions. Importantly, we find Sherloc interpretations to be highly consistent with those submitted to ClinVar.