Abstract
Introduction
Classification of variants of unknown significance (VUS) in the breast cancer genes BRCA1 and BRCA2 changes with accumulating evidence for clinical relevance. In most cases down-staging towards neutral variants without clinical significance is possible.
Methods
We searched the database of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) for changes in classification of genetic variants as an update to our earlier publication on genetic variants in the Centre of Dresden. Changes between 2015 and 2017 were recorded.
Results
In the group of variants of unclassified significance (VUS, Class 3, uncertain), only changes of classification towards neutral genetic variants were noted. In BRCA1, 25% of the Class 3 variants (n = 2/8) changed to Class 2 (likely benign) and Class 1 (benign). In BRCA2, in 50% of the Class 3 variants (n = 16/32), a change to Class 2 (n = 10/16) or Class 1 (n = 6/16) was observed. No change in classification was noted in Class 4 (likely pathogenic) and Class 5 (pathogenic) genetic variants in both genes. No up-staging from Class 1, Class 2 or Class 3 to more clinical significance was observed.
Conclusion
All variants with a change in classification in our cohort were down-staged towards no clinical significance by a panel of experts of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Prevention in families with Class 3 variants should be based on pedigree based risks and should not be guided by the presence of a VUS.
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Funding
German Cancer Aid Grant No. 110837 for GC-HBOC.
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KK: conception of the work, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, and final approval of the version to be published. PW: critical revision of the manuscript for important intellectual content, and final approval of publication. NA: interpretation of data, critical revision of the manuscript for important intellectual content, and final approval of publication.
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The authors declare that they have no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (No. EK 162072007) and with the 1064 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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Informed consent was obtained from all individual participants included in the study.
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Kast, K., Wimberger, P. & Arnold, N. Changes in classification of genetic variants in BRCA1 and BRCA2. Arch Gynecol Obstet 297, 279–280 (2018). https://doi.org/10.1007/s00404-017-4631-2
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DOI: https://doi.org/10.1007/s00404-017-4631-2