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Substantial evidence for the clinical significance of missense variant BRCA1 c.5309G>T p.(Gly1770Val)

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Abstract

Purpose

Classification of rare BRCA1 missense variants presents a major challenge for the counseling and treatment of patients. Variant classification can be complicated by conflicting lines of evidence. BRCA1 c.5309G>T p.(Gly1770Val) has been shown to abrogate BRCA1 protein homologous DNA repair; however, multiple sequence alignment demonstrates a lack of sequence conservation at this position, suggesting that glycine at position 1770 may not be essential for cellular maintenance in humans. We analyzed clinical information to resolve the classification of BRCA1 c.5309G>T p.(Gly1770Val).

Methods

We performed multifactorial likelihood analysis combining segregation data for 14 informative families, and breast tumor histopathological data for 17 variant carriers, ascertained through the ENIGMA consortium.

Results

Bayes segregation analysis gave a likelihood ratio of 101:1 in favor of pathogenicity. The vast majority of breast tumors showed features indicative of pathogenic variant carrier status, resulting in a likelihood ratio of 15800794:1 towards pathogenicity. Despite a low prior probability of pathogenicity (0.03) based on bioinformatic prediction, multifactorial likelihood analysis including segregation and histopathology analysis gave a posterior probability of > 0.99 and final classification of Pathogenic.

Conclusions

We provide evidence that BRCA1 c.5309G>T p.(Gly1770Val), previously described as a Moroccan founder variant, should be treated as a disease-causing variant despite a lack of evolutionary conservation at this amino acid position. Additionally, we stress that bioinformatic information should be used in combination with other data, either direct clinical evidence or some form of clinical calibration, to arrive at a final clinical classification.

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Acknowledgements

We thank the families who contributed to this study. We thank Sean Tavtigian for his helpful advice regarding sequence conservation comparisons and members of the ENIGMA steering committee for critique on this manuscript. We thank Kathleen Claes and Nora Martinussen Tandstad for contributing data from Belgium and Norway respectively. ET is supported by a grant from the National Health and Medical Research Council (ID1104808). SM was supported by the Netherlands Organization for Scientific Research (NWO), research program Mosaic (Grant 017.008.022) and Van de Kampfonds from Leiden University Medical Centre (Grant 30.925). MTP is supported by a grant from Newcastle University, UK and ABS by an NHMRC Senior Research Fellowship (ID1061779). CL wishes to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. CL is supported by the Carlos III Health Institute funded by FEDER funds – a way to build Europe – [PI16/00563 and CIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en salut (PERIS), 2017SGR1282 and 2017SGR496]; and the Scientific Foundation Asociación Española Contra el Cáncer.

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Author notes

  1. Emma Tudini and Setareh Moghadasi contributed equally to this study.

Authors and Affiliations

  1. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia

    Emma Tudini, Michael T. Parsons & Amanda B. Spurdle

  2. Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands

    Setareh Moghadasi

  3. Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Lizet van der Kolk

  4. Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Ans M. W. van den Ouweland

  5. Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

    Dieter Niederacher

  6. Molecular Diagnostic Unit, Hereditary Cancer and Ocobell Programs, IDIBELL, Catalan Institute of Oncology, Barcelona, Spain

    Lídia Feliubadaló & Conxi Lazaro

  7. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain

    Lídia Feliubadaló & Conxi Lazaro

  8. Centre of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany

    Barbara Wappenschmidt

  9. Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany

    Barbara Wappenschmidt

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  1. Emma Tudini
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  2. Setareh Moghadasi
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  3. Michael T. Parsons
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  4. Lizet van der Kolk
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  5. Ans M. W. van den Ouweland
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  9. Amanda B. Spurdle
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  10. Conxi Lazaro
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Corresponding authors

Correspondence to Amanda B. Spurdle or Conxi Lazaro.

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The authors declare that they have no conflict of interest.

Ethical approval

Families were ascertained as part of an ENIGMA consortium project. Each contributing center had ethical approval to recruit consenting individuals from families for the purpose of aiding variant classification. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Tudini, E., Moghadasi, S., Parsons, M.T. et al. Substantial evidence for the clinical significance of missense variant BRCA1 c.5309G>T p.(Gly1770Val). Breast Cancer Res Treat 172, 497–503 (2018). https://doi.org/10.1007/s10549-018-4903-y

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  • DOI: https://doi.org/10.1007/s10549-018-4903-y

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