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Klassifizierung von „variants of unknown significance“ (VUS) beim familiären Brust- und Eierstockkrebs

Classification of variants of unknown significance (VUS) in hereditary breast and ovarian cancer

Zusammenfassung

Die Anwendung von NGS-basierten Verfahren in der molekulargenetischen Diagnostik wird in den nächsten Jahren zur Identifikation einer Vielzahl von Varianten mit unklarer Signifikanz (VUS) führen, deren Relevanz für den untersuchten Phänotyp bestimmt werden muss. In der Diagnostik erblicher Tumorprädispositionserkrankungen wird die VUS-Klassifizierung insbesondere in non-BRCA1/2-Genen in den nächsten Jahren einen hohen Stellenwert einnehmen, eine Herausforderung, die jedoch insbesondere durch internationale wissenschaftliche Kooperationen bewältigt werden kann. Das Deutsche Konsortium Familiärer Brust- und Eierstockkrebs (GC-HBOC) verwendet zur Klassifikation dieser Varianten das international etablierte IARC 5-Klassen-System und kooperiert zur Bewertung seltener Varianten sowie Varianten in bislang weniger gut untersuchten Genen mit zahlreichen internationalen Konsortien und Forschungsgruppen. Vorhersageprogramme können im Kontext von Forschungsprojekten ein nützliches Werkzeug bei der Bewertung beispielsweise der großen Zahl von Varianten in NGS-basierten Untersuchungen sein. Im Rahmen der molekulargenetischen Diagnostik sollte die Klassifizierung der identifizierten Varianten jedoch nicht ausschließlich aufgrund der Vorhersageprogramme erfolgen.

Abstract

In the coming years, procedures based on next-generation sequencing (NGS) in genetic routine diagnostics will lead to a tremendous increase in the number of identified variants of unknown significance (VUS) whose relevance for the analysed phenotype has to be determined. Classification of VUS, especially in non-BRCA1/2 genes, will become one of the key challenges in diagnostics of hereditary tumor predisposition disorders. These can be overcome by international scientific cooperation. Therefore, the German consortium of hereditary breast and ovarian cancer (GC-HBOC) applies the internationally accepted IARC 5-class system and cooperates with numerous international consortia and working groups for the classification of infrequent variants and variants in new risk genes. Prediction programs can be valuable tools for classification of variants especially in the context of NGS-based research projects dealing with large amounts of data. In a diagnostic setting, the classification of variants should not be solely based on in-silico prediction tools.

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Correspondence to Jan Hauke.

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Interessenkonflikt

PD Dr. Eric Hahnen weist auf folgende Beziehung hin: Er erhielt Honorare für die Teilnahme an Scientific Advisory Board Treffen der Firma AstraZeneca. Jan Hauke, Christoph Engel, Barbara Wappenschmidt und Clemens R. Müller geben an, dass kein Interessenkonflik besteht.

Alle im vorliegenden Manuskript beschriebenen Untersuchungen am Menschen wurden mit Zustimmung der zuständigen Ethik-Kommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki von 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt. Von allen beteiligten Patienten liegt eine Einverständniserklärung vor.

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Hauke, J., Engel, C., Wappenschmidt, B. et al. Klassifizierung von „variants of unknown significance“ (VUS) beim familiären Brust- und Eierstockkrebs. medgen 27, 211–216 (2015). https://doi.org/10.1007/s11825-015-0049-z

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Schlüsselwörter

  • VUS
  • Vorhersageprogramme
  • Klassifizierung
  • Mutation
  • Panelanalyse

Keywords

  • VUS
  • Prediction tools
  • Classification
  • Mutation
  • Panel analysis