Hereditary breast and ovarian cancer syndrome is an autosomal dominant disease caused primarily by germline mutations in the BRCA1 or BRCA2 gene. Rare cases of double heterozygosity for BRCA1 and BRCA2 mutations have been reported quite exceptionally in non-Ashkenazi individuals. We describe the case of a woman who developed a bilateral breast cancer, discovered concomitantly, at 46 years old. Biopsies confirmed the presence of two breast cancers with distinct histology. BRCA analysis was tested due to a positive family history of breast cancer, and two pathogenic monoallelic mutations were detected, one in the BRCA1 gene and one in the BRCA2 gene. There is no known Ashkenazi Jewish ancestry. We report the first description of a never described double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient, with two distinct histology, and two distinct mutations.

Double heterozygosity is an extremely rare occurrence in hereditary breast and ovarian cancer syndrome (HBOC [MIM 604370; MIM 612555]) where two pathogenic variants, one in BRCA1 and one in BRCA2, are found in an individual. To date, only a few case reports and case series have been reported in the literature (1-3). Furthermore, little is known about the clinical characteristics, family history, and tumor histology in these patients. In this study, we utilized targeted gene testing with next-generation sequencing (NGS) technology in an early-onset metastatic breast cancer patient from France. We evaluated germline variants using Pathway Genomics' BRCATrueTM NGS test, which analyzes variants covering all exons and exon flanking regions in both the BRCA1 and BRCA2 genes. All variant calls were determined after alignment and mapping to the GRCh37/hg19 reference genome. Variant calls were confirmed by Sanger sequencing. In this patient, a c.1016dupA (p.V340GfsX6) frameshift variant was found in BRCA1 along with a c.6814delA (p.R2272EfsX8) frameshift variant in BRCA2. Both frameshift variants are predicted to truncate the BRCA proteins. The BRCA1 c.1016dupA variant is considered a Norwegian founder mutation but has also been observed in individuals who are of French-Canadian, French, Italian or Dutch ancestry (4-7). The BRCA2 c.6814delA (p.R2272Efs*8) pathogenic variant, also known as 7042delA, is predicted to truncate the BRCA2 protein and has been identified in individuals with a personal or family history of breast and/or ovarian cancer (8,9). To the best of our knowledge, the combination of these two pathogenic variants in an individual has not been previously reported. In a clinical diagnostic setting, the possibility of double heterozygosity of pathogenic variants in more than one susceptibility gene should be considered, especially in patients with early-onset metastatic cancers. Furthermore, genetic testing and genetic counseling should also be indicated for high-risk family members. 1. Heidemann, S. et al. (2012) Breast cancer research and treatment 134, 1229-1239 2. Lavie, O., et al. (2011) Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 22, 964-966 3. Nomizu, T., et al. (2012). Breast cancer 4. Andersen, T. I., Borresen, A. L., and Moller, P. (1996) American journal of human genetics 59, 486-487 5. Caputo, S., et al. (2012) Nucleic acids research 40, D992-1002 6. Dorum, A., et al. (1999). American journal of human genetics 65, 671-679 7. Simard, J., et al. (1994). Nature genetics 8, 392-398 8. Novakovic, S., et al. (2012) International journal of oncology 41, 1619-1627 9. Tea, M. K., et al. (2014) Maturitas 77, 68-72. Citation Format: Curtit E, Meynard G, Villanueva C, Mansi L, Chaix M, Vilalta A, Kuo JZ, Villa M, Neidich J, Tomar A, Arianpour A, Lebahar P, Pivot X. Double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-10.