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Cancers 2019, 11(2), 132; https://doi.org/10.3390/cancers11020132

Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift

1
Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo 0424, Norway
2
Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal 42283, Germany
3
Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo 0424, Norway
4
Center for Bioinformatics, Department of Informatics, University of Oslo, PO box 1080, Blindern 0316 OSLO, Norway
*
Author to whom correspondence should be addressed.
Received: 17 December 2018 / Revised: 17 January 2019 / Accepted: 20 January 2019 / Published: 23 January 2019
(This article belongs to the Special Issue BRCA Mutations and Cancer)
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Abstract

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10–30%), compared to 35% (95% confidence interval 22–48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32–39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy. View Full-Text
Keywords: pathogenic BRCA1 variants; founder variants; fitness; genetic epidemiology; genetic drift; hot-spots germline mutations. pathogenic BRCA1 variants; founder variants; fitness; genetic epidemiology; genetic drift; hot-spots germline mutations.
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Møller, P.; Dominguez-Valentin, M.; Rødland, E.A.; Hovig, E. Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift. Cancers 2019, 11, 132.

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