| Title: |
Evidence for pathogenicity of BRCA2 c.8351G>A p.(Arg2784Gln) and the challenges in classification of pathogenic variants with reduced penetrance |
| Authors: |
Moghadasi, S.; Zanti, M.; Bleeker, F.; Blok, M.; Braspenning, M.E.; Cerna, M.; Collee, M.J.; Engel, C.; Hopman, S.; Kleiblova, P.; Koole, W.; Mensenkamp, A.; Overwater, E.; Palmero, E.I.; Blok, L.S.; Storm, K.; Stringa, N.; Wevers, M.R.; Vreeswijk, M.P.G.; Goldgar, D.; Michailidou, K.; García, E.B.G. |
| Source: |
Journal of Medical Genetics |
| Publication Year: |
2025 |
| Collection: |
Leiden Repository (Leiden University) |
| Subject Terms: |
Genetics; Medical; Disease Management; Genetic Variation |
| Description: |
Background: The BRCA2 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: Co-segregation analysis using a grid search across scaled penetrance levels for BRCA2 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. 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: Our results indicate that BRCA2 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 ATM and CHEK2. 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. ; Genome Instability and Cancer |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://hdl.handle.net/1887/4297936 |
| DOI: |
10.1136/jmg-2025-111145 |
| Availability: |
https://hdl.handle.net/1887/4297936; https://doi.org/10.1136/jmg-2025-111145 |
| Accession Number: |
edsbas.EC8975D |
| Database: |
BASE |