Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer

Abstract

BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi Anemia and predisposition to cancers, while biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance (VUS) in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala co-segregated with cancer in multiple families, associated tumors demonstrated loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations, and have implications for the interpretation of genetic test results.

A High-Throughput Functional Complementation Assay for Classification ofBRCA1Missense Variants

“…S4F, S1651P, S1651F, V1736A, H1746Q, and R1753T were differently classifi ed in repeat experiments, which may refl ect technical fl aws or intermediate activity of these variants. Of note, the V1736A mutation was recently identifi ed as a pathogenic variant with hypomorphic activity in DNA repair ( 31 ). Although we did not measure signifi cant HR activity of V1736A in a DR-GFP gene conversion assay, intermediate activity of this variant is supported by the results of the proliferation assays and additional cisplatin sensitivity assays.…”

“…We therefore tested complementation of PARP inhibitor sensitivity for a number of BRCA1 mutants and the BRCA1 wild-type control. Given the unexpected neutral effects of the M1400V, L1407P, and M1411T mutations in the PALB2 interaction domain, we decided to include these variants in this series, as well as the R1699Q and V1736A variants that have recently been shown to confer (intermediate) breast and ovarian cancer risk ( 31,32 ). To allow direct comparison of results from different assays, we repeated the cisplatin sensitivity and proliferation assays in parallel to the olaparib sensitivity assay.…”

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…More recently, it has been recognized that mutation carriers of some of the FA genes (e.g., parents of the FA patients) may actually develop HBOC and that the other HBOC genes (i.e., BRCA1 (Domchek et al 2013, Sawyer et al 2015) can cause an FA-like disorder when biallelically mutated (Bogliolo & Surrallés 2015). Thus, HBOC and the FA genes do overlap to some extent (Tables 1 and 2).…”

“…, Bogliolo & Surrallés 2015, Ceccaldi et al 2016. BRCA1/FANCS (Domchek et al 2013, Sawyer et al 2015 and RAD51/FANCR (Ameziane et al 2015, Wang et al 2015 genes are recent and surprising additions to this group. Many of these are HBOC genes (Table 1) and RAD51 mediators.…”

“…Recently, biallelic mutations in the BRCA1 gene have finally been identified in two patients with early-onset ovarian or breast cancer (Domchek et al 2013, Sawyer et al 2015. Diepoxybutane (DEB) induced chromosome breakage test was performed in one of them and found to be positive (Domchek et al 2013, Sawyer et al 2015, leading to the designation of FANCS.…”