Aktualisierte Kriterien des Deutschen Konsortiums Familiärer Brust- und Eierstockkrebs zur Klassifizierung von Keimbahn-Sequenzvarianten in Risikogenen für familiären Brust- und Eierstockkrebs

Zusammenfassung

Das Deutsche Konsortium für Familiären Brust- und Eierstockkrebs (GC-HBOC) etablierte vor über 10 Jahren eine Expertengruppe (VUS Task Force), um die von Einzelzentren des GC-HBOC an die zentrale Datenbank in Leipzig gemeldeten Genvarianten hinsichtlich ihrer Klassifizierung zu überprüfen und ggf. nach aktueller Datenlage neu einzustufen. Die innerhalb der VUS Task Force konsentierten Variantenbewertungen und resultierenden Klassifizierungen werden in einer zentralen Datenbank (Heredicare) hinterlegt. Sie sind als Grundlage zu berücksichtigen, um eine einheitliche Bewertung bereits bekannter wie auch neu identifizierter Varianten innerhalb des GC-HBOC zu gewährleisten. Die standardisierte VUS-Bewertung durch die VUS Task Force ist ein zentrales Element des vom GC-HBOC ebenfalls etablierten Recall-Systems. Dieses dient der Weitergabe der Informationen an die genetischen Berater der in den Zentren betreuten Familien im Falle einer aufgrund neuer Erkenntnisse aktualisierten Bewertung bereits klassifizierter Varianten. Die mit international etablierten Bewertungsverfahren (IARC, ACMG, ENIGMA) harmonisierten Bewertungsalgorithmen der VUS Task Force werden in diesem Artikel anhand der zugrunde liegenden Entscheidungskriterien präsentiert, die mittels eines priorisierenden Fließschemas zum Klassifizierungsergebnis führen. Weiterhin werden genspezifische Regelungen und Besonderheiten, die für einzelne mit Brust- und/oder Eierstockkrebs assoziierte Risikogene zu berücksichtigen sind, in einzelnen Unterkapiteln dargelegt. Um dem Umfang und der Dynamik des aktuellen Wissens zur Variantenbewertung gerecht zu werden, sind neben umfangreichen Literaturverweisen insbesondere auch die URLs von relevanten Datenbanken angegeben. In Zukunft sollen die an neue Erkenntnisse angepassten Kriterien auf der Webseite des GC-HBOC (https://www.konsortium-familiaerer-brustkrebs.de/) veröffentlicht werden und als Grundlage für die automatisierte Bewertung von Varianten dienen. Dies ist Bestandteil des durch die Deutsche Krebshilfe geförderten Forschungsvorhabens HerediVar. Des Weiteren werden die so vom Expertengremium bewerten Varianten zukünftig in der ClinVar-Datenbank hinterlegt, um sie international zugänglich zu machen.

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 at 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 (HerediCare) 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 the information to the geneticcounselors of the families monitored and managed by GC-HBOCcentres in the event of an updated re-evaluation of previously classified variants based on new information. The evaluation algorithm of the VUS Task Force was adapted to internationally established assessment methods (IARC, ACMG, ENIGMA) and is presented here together with the underlying decision-criteria used to arrive at the classification result according to a prioritizing 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 dynamics of the current knowledge on the evaluation of genetic variants. In the future, the criteria adapted to new findings are to be published on the GC-HBOC website (https://www.konsortium-familiaerer-brustkrebs.de/) and serve as a basis for the automated evaluation of variants. This is part of the HerediVar research project funded by the German Cancer Aid. Furthermore, the variants evaluated by the expert panel are to be stored in the ClinVar database in the future in order to make them internationally accessible.

Schlüsselwörter

familiärer Brust-/Eierstockkrebs - Klassifikation genetischer Varianten - Risikogene

Key words

hereditary breast/ovarian cancer - classification of genetic variants - risk genes

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