J Breast Cancer.  2017 Sep;20(3):310-313. 10.4048/jbc.2017.20.3.310.

A Novel Germline Mutation in BRCA1 Causes Exon 20 Skipping in a Korean Family with a History of Breast Cancer

  • 1Department of Biochemistry, College of Veterinary Medicine, Konkuk University, Seoul, Korea.
  • 2Genetic Counseling Clinic, National Cancer Center Hospital, National Cancer Center, Goyang, Korea.
  • 3Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
  • 4Translational Epidemiology Branch, National Cancer Center Research Institute, National Cancer Center, Goyang, Korea.
  • 5Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. suhwan.chang@amc.seoul.kr
  • 6Center for Breast Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, Korea.
  • 7Precision Medicine Branch, National Cancer Center Research Institute, National Cancer Center, Goyang, Korea.


Germline mutations in the BRCA1 and BRCA2 genes are strong genetic factors for predispositions to breast, ovarian, and other related cancers. This report describes a family with a history of breast and ovarian cancers that harbored a novel BRCA1 germline mutation. A single nucleotide deletion in intron 20, namely c.5332+4delA, was detected in a 43-year-old patient with breast cancer. This mutation led to the skipping of exon 20, which in turn resulted in the production of a truncated BRCA1 protein that was 1773 amino acids in length. The mother of the proband had died due to ovarian cancer and had harbored the same germline mutation. Ectopically expressed mutant BRCA1 protein interacted with the BARD1 protein, but showed a reduced transcriptional function, as demonstrated by the expression of cyclin B1. This novel germline mutation in the BRCA1 gene caused familial breast and ovarian cancers.


BRCA1 protein; Breast neoplasms; Germ-line mutation

MeSH Terms

Amino Acids
BRCA1 Protein
Breast Neoplasms*
Cyclin B1
Genes, BRCA1
Genes, BRCA2
Germ-Line Mutation*
Ovarian Neoplasms
Amino Acids
BRCA1 Protein
Cyclin B1


  • Figure 1 Pedigree of the patient's family, showing multiple individuals with breast and ovarian cancer. The proband (arrow) and her family members harboring the mutation (c.5332+4delA) in BRCA1 gene are marked in red. Male is represented by a square and female by a circle. Numbers in parentheses indicate age at cancer diagnosis.

  • Figure 2 Mutation analysis of exon 20 in BRCA1 gene. (A) Sequence analysis of the mutant BRCA1 gene shows a deletion in c.5332+4delA (genomic DNA) and exon 20 skipping (RNA). Exon 20 sequences are colored in yellow. (B) The schematic view shows the variant localization and the mutated mRNA skipping 55 bp of exon 20.

  • Figure 3 Functional analyses of mutant BRCA1 protein. (A) Mutant BRCA1 protein (exon 20 deletion) showed reduced protein level. BRCA1-deficient MDA-MB-436 cells were transfected with a vector expressing HA-tagged BRCA1 wild-type (WT) or exon20 skipping mutant or untagged mutant BRCA1 (exon 20 deletion) mRNA. A point mutation of BRCA1 that causes an amino acid substitution of leucine to phenylalanine (L52F) was used as a missense mutant control. After 24 hours, the cells were treated with DMSO (control) or MG132 (1 µM). The arrows indicate BRCA1 protein and the asterisk indicates a nonspecific band. (B) WT or mutant BRCA1 is immunoprecipitated with anti-BARD1 antibody. Immunoprecipitated WT and mutant BRCA1 were detected by Western blotting with an anti-BRCA1 antibody (boxed lane). (C) Expression level of cyclin B1 was compared among cells transfected with WT or mutant BRCA1. Relative expression of cyclin B1 was measured by real-time reverse transcription polymerase chain reaction compared to glyceraldehyde 3-phosphate dehydrogenase after exogenous expression of WT or mutant BRCA1. DMSO=dimethyl sulfoxide; Ex20del=exon 20 deletion; BARD1=BRCA1 associated RING domain1; GFP=green fluoresence protein (control DNA); IP=immunoprecipitation; IB=immunoblotting. *Nonspecific band.


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