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Precision Medicine and Imaging

Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays

Peter Bouwman, Ingrid van der Heijden, Hanneke van der Gulden, Roebi de Bruijn, Merel E. Braspenning, Setareh Moghadasi, Lodewyk F.A. Wessels, the Dutch-Belgian VUS workgroup, Maaike P.G. Vreeswijk and Jos Jonkers
Peter Bouwman
1Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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  • For correspondence: j.jonkers@nki.nl p.bouwman@nki.nl
Ingrid van der Heijden
1Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Hanneke van der Gulden
1Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Roebi de Bruijn
1Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
2Oncode Institute and Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Merel E. Braspenning
3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
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Setareh Moghadasi
4Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
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Lodewyk F.A. Wessels
2Oncode Institute and Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Maaike P.G. Vreeswijk
3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
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Jos Jonkers
1Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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  • For correspondence: j.jonkers@nki.nl p.bouwman@nki.nl
DOI: 10.1158/1078-0432.CCR-20-0255 Published September 2020
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Abstract

Purpose: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway.

Experimental Design: Two hundred thirty-eight BRCA1 VUS—comprising most BRCA1 VUS known in the Netherlands and Belgium—were tested for their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families.

Results: All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%–100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants.

Conclusions: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:4559–68

  • Received January 21, 2020.
  • Revision received April 29, 2020.
  • Accepted June 12, 2020.
  • Published first June 16, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (17)
September 2020
Volume 26, Issue 17
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Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays
Peter Bouwman, Ingrid van der Heijden, Hanneke van der Gulden, Roebi de Bruijn, Merel E. Braspenning, Setareh Moghadasi, Lodewyk F.A. Wessels, the Dutch-Belgian VUS workgroup, Maaike P.G. Vreeswijk and Jos Jonkers
Clin Cancer Res September 1 2020 (26) (17) 4559-4568; DOI: 10.1158/1078-0432.CCR-20-0255

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Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays
Peter Bouwman, Ingrid van der Heijden, Hanneke van der Gulden, Roebi de Bruijn, Merel E. Braspenning, Setareh Moghadasi, Lodewyk F.A. Wessels, the Dutch-Belgian VUS workgroup, Maaike P.G. Vreeswijk and Jos Jonkers
Clin Cancer Res September 1 2020 (26) (17) 4559-4568; DOI: 10.1158/1078-0432.CCR-20-0255
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