Evidence for pathogenicity of <i>BRCA2</i> c.8351G>A p.(Arg2784Gln) and the challenges in classification of pathogenic variants with reduced penetrance
Our results indicate that <i>BRCA2</i> c.8351G>A p.(Arg2784Gln) has a disease-causing effect, with reduced penetrance, similar to other pathogenic variants in moderate risk breast cancer genes such as <i>ATM</i> and <i>CHEK2</i>. We also provide risk-adapted recommendations for clinical management. Importantly, one should be aware of a reduced penetrance as the underlying reason for conflicting results among pieces of evidence used for variant classification.
Authors
- E. Gómez (ORCID: https://orcid.org/0000-0003-4999-8847)
- Eline Overwater (ORCID: https://orcid.org/0000-0002-0993-5035)
- Arjen R. Mensenkamp (ORCID: https://orcid.org/0000-0003-3805-877X)
- Christoph Engel (ORCID: https://orcid.org/0000-0002-7247-282X)
- Najada Stringa (ORCID: https://orcid.org/0000-0001-6350-452X)
- Marinus J. Blok (ORCID: https://orcid.org/0000-0002-7935-5933)
- Petra Kleiblová (ORCID: https://orcid.org/0000-0002-4806-9854)
- Kyriaki Michailidou (ORCID: https://orcid.org/0000-0001-7065-1237)
- Maaike P.G. Vreeswijk (ORCID: https://orcid.org/0000-0003-4068-9271)
- Wouter Koole (ORCID: https://orcid.org/0000-0002-8065-0630)
- Marta Černá
- Maria Zanti (ORCID: https://orcid.org/0000-0002-0136-9921)
- Edenir Inêz Palmero (ORCID: https://orcid.org/0000-0003-1904-2158)
- Fonnet E. Bleeker (ORCID: https://orcid.org/0000-0002-9337-6909)
- Saskia Hopman
- Lot Snijders Blok (ORCID: https://orcid.org/0000-0002-9825-3625)
- Merel E. Braspenning
- Marijke R. Wevers (ORCID: https://orcid.org/0000-0001-8008-6008)
- Margriet J Collée
- David E. Goldgar
- Katrien Storm (ORCID: https://orcid.org/0000-0002-4128-0454)
- Setareh Moghadasi (ORCID: https://orcid.org/0000-0001-7711-1030)
Institutions
- University Medical Center Groningen (NL)
- Radboud University Nijmegen (NL)
- University of Antwerp (BE)
- Charles University (CZ)
- Leiden University Medical Center (NL)
- Huntsman Cancer Institute (US)
- Radboud University Medical Center (NL)
- The Netherlands Cancer Institute (NL)
- University Medical Center Utrecht (NL)
- Maastricht University (NL)
- Hospital de Câncer de Barretos (BR)
- Antwerp University Hospital (BE)
- Instituto Nacional de Câncer - INCA (BR)
- Erasmus MC Cancer Institute (NL)
- Amsterdam University Medical Centers (NL)
- General University Hospital in Prague (CZ)
- Cyprus Institute of Neurology and Genetics (CY)
- University of Amsterdam (NL)
- Leipzig University (DE)
Publication Details
- Journal
- Journal of Medical Genetics
- Published
- 2025-12-18
- DOI
- https://doi.org/10.1136/jmg-2025-111145
- Primary Topic
- BRCA gene mutations in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00