Keupp, Katharina, Hampp, Stephanie, Huebbel, Annette, Maringa, Monika, Kostezka, Sarah, Rhiem, Kerstin, Waha, Anke, Wappenschmidt, Barbara, Pujol, Roser, Surralles, Jordi, Schmutzler, Rita K., Wiesmueller, Lisa and Hahnen, Eric (2019). Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia-like phenotype, and no chromosome fragility. Mol. Genet. Genom. Med., 7 (9). HOBOKEN: WILEY. ISSN 2324-9269

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Keupp, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hampp, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huebbel, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maringa, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kostezka, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rhiem, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waha, AnkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pujol, RoserUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surralles, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesmueller, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-134643
DOI: 10.1002/mgg3.863
Journal or Publication Title: Mol. Genet. Genom. Med.
Volume: 7
Number: 9
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 2324-9269
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
OVARIAN; REPAIR; CLASSIFICATION; VARIANTSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13464

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