Evidence for pathogenicity of BRCA2 c.8351G>A p.(Arg2784Gln) and the challenges in classification of pathogenic variants with reduced penetrance
Year: 2025
Type: article
Study design: Observational Study
Abstract: BACKGROUND: c.8351G>A p.(Arg2784Gln) variant has long been classified as a variant of uncertain significance (VUS) due to conflicting evidence used in variant classification. This study aims to clarify its pathogenicity and associated risks for breast and ovarian cancer. METHODS: This study was conducted by the international Evidence-based Network for the Interpretation of Germline Mutant Alleles consortium. We collected data from 29 informative families with this variant. Co-segregation likelihood ratios (LRs) were calculated using the full-likelihood method to assess pathogenicity, and cancer risks were estimated with modified segregation analysis. RESULTS: truncating variants yielded the strongest evidence in favour of pathogenicity, with LR maximised at approximately 20% of full penetrance (LR=11.026). Furthermore, estimated breast cancer risks were markedly higher for early onset breast cancer; women diagnosed at <50 years had a HR of 4.5, compared with a HR of 1.65 for women diagnosed at ≥50 years. The estimated lifetime risks were 25% for breast cancer and 6% for ovarian cancer.Evidence of pathogenicity was also supported by the presence of the variant allele in two patients with Fanconi anaemia. CONCLUSIONS: . 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.
Source: Journal of Medical Genetics
Authors: Setareh Moghadasi, Maria Zanti, Fonnet Bleeker, Marinus Blok, Merel E Braspenning, Marta Cerna, Margriet J Collee, Christoph Engel, Saskia Hopman, Petra Kleiblova, Wouter Koole, Arjen Mensenkamp, Eline Overwater, Edenir Inez Palmero, Lot Snijders Blok, Katrien Storm, Najada Stringa, Marijke R Wevers, Maaike P G Vreeswijk, David Goldgar, Kyriaki Michailidou, Encarna B Gómez García
Institutions: Leiden University Medical Center, Cyprus Institute of Neurology and Genetics, The Netherlands Cancer Institute, Maastricht University Medical Centre, Maastricht University, Charles University, General University Hospital in Prague, Erasmus MC, Erasmus MC Cancer Institute, Leipzig University, University Medical Center Utrecht, Radboud University Medical Center, University Medical Center Groningen, Hospital de Câncer de Barretos, Instituto Nacional de Câncer - INCA, University of Antwerp, Antwerp University Hospital, Amsterdam University Medical Centers, University of Utah, Huntsman Cancer Institute
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G117134978, G157158208, G1735209766, G2270929433, G2868665970, G3098558563, Verbetering van de interpretatie van de DNA-uitslag bij erfelijk borst- en eierstokkanker door het gebruik van functionele gen-testen, G3630972281, Molecular characterization of at high risk families for hereditary breast cancer, negatives for BRCA1/BRCA2: looking for the BRCAx
OpenAlex ID: W4417469598