Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia-like phenotype, and no chromosome fragility

Katharina Keupp, Stephanie Hampp, Annette Hübbel, Monika Maringa, Sarah Kostezka, Kerstin Rhiem, Anke Waha, Barbara Wappenschmidt, Roser Pujol, Jordi Surrallés, Rita K. Schmutzler, Lisa Wiesmüller, Eric Hahnen

Research output: Contribution to journalArticleResearch

3 Citations (Scopus)

Abstract

© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Biallelic BRCA1 mutations are regarded either embryonically lethal or to cause Fanconi anemia (FA), a genomic instability syndrome characterized by bone marrow failure, developmental abnormalities, and cancer predisposition. We report biallelic BRCA1 mutations c.181T > G (p.Cys61Gly) and c.5096G > A (p.Arg1699Gln) in a woman with breast cancer diagnosed at the age of 30 years. The common European founder mutation p.Cys61Gly confers high cancer risk, whereas the deleterious p.Arg1699Gln is hypomorphic and was suggested to confer intermediate cancer risk. Methods and Results: Aside from significant toxicity from chemotherapy, the patient showed mild FA-like features (e.g., short stature, microcephaly, skin hyperpigmentation). Chromosome fragility, a hallmark of FA patient cells, was not present in patient-derived peripheral blood lymphocytes. We demonstrated that the p.Arg1699Gln mutation impairs DNA double-strand break repair, elevates RAD51 foci levels at baseline, and compromises BRCA1 protein function in protecting from replication stress. Although the p.Arg1699Gln mutation compromises BRCA1 function, the residual activity of the p.Arg1699Gln allele likely prevents from chromosome fragility and a more severe FA phenotype. Conclusion: Our data expand the clinical spectrum associated with biallelic BRCA1 mutations, ranging from embryonic lethality to a mild FA-like phenotype and no chromosome fragility.
Original languageEnglish
Article numbere863
JournalMolecular Genetics and Genomic Medicine
Volume7
DOIs
Publication statusPublished - 1 Sep 2019

Keywords

  • biallelic BRCA1
  • early onset breast cancer
  • Fanconi anemia
  • p.Arg1699Gln

Fingerprint Dive into the research topics of 'Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia-like phenotype, and no chromosome fragility'. Together they form a unique fingerprint.

Cite this