Criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for the Classification of Germline Sequence Variants in Risk Genes for Hereditary Breast and Ovarian Cancer

Abstract

More than ten years ago, the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) set up a panel of experts (VUS Task Force) which was tasked with reviewing the classifications of genetic variants reported by individual centres of the GC-HBOC to the central database in Leipzig and reclassifying them, where necessary, based on the most recent data. When it evaluates variants, the VUS Task Force must arrive at a consensus. The resulting classifications are recorded in a central database where they serve as a basis for ensuring the consistent evaluation of previously known and newly identified variants in the different centres of the GC-HBOC. The standardised VUS evaluation by the VUS Task Force is a key element of the recall system which has also been set up by the GC-HBOC. The system will be used to pass on information to families monitored and managed by GC-HBOC centres in the event that previously classified variants are reclassified based on new information. The evaluation algorithm of the VUS Task Force was compiled using internationally established assessment methods (IARC, ACMG, ENIGMA) and is presented here together with the underlying evaluation criteria used to arrive at the classification decision using a flow chart. In addition, the characteristics and special features of specific individual risk genes associated with breast and/or ovarian cancer are discussed in separate subsections. The URLs of relevant databases have also been included together with extensive literature references to provide additional information and cover the scope and dynamism of the current state of knowledge on the evaluation of genetic variants. In future, if criteria are updated based on new information, the update will be published on the website of the GC-HBOC (http://www.konsortium-familiaerer-brustkrebs.de/).