Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation

What is it about?

Clinical tests to identify gene variants linked to hereditary breast and ovarian cancer susceptibility have become widely available. Determination of whether or not a variant is associated with disease relies on painstaking family-based segregation analyses. However, the rapid increase in usage of clinical DNA tests has led to the discovery of a large number of variants of uncertain clinical significance (VUS). For most VUS there is insufficient information for family-based analysis and therefore use of protein functional assays in the laboratory is increasingly being used to support clinical annotation. Here we use the lessons learned from BRCA1 and BRCA2 to identify best practices for the use of functional assays for clinical annotation of variants. We provide recommendations for the interpretation and use of established functional assays as well as for the development of new assays.

Featured Image