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Case Reports
. 2013 Apr;3(4):399-405.
doi: 10.1158/2159-8290.CD-12-0421. Epub 2012 Dec 26.

Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer

Susan M Domchek  1 , Jiangbo Tang, Jill Stopfer, Dana R Lilli, Nancy Hamel, Marc Tischkowitz, Alvaro N A Monteiro, Troy E Messick, Jacquelyn Powers, Alexandria Yonker, Fergus J Couch, David E Goldgar, H Rosemarie Davidson, Katherine L Nathanson, William D Foulkes, Roger A Greenberg
Affiliations
Case Reports

Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer

Susan M Domchek et al. Cancer Discov. 2013 Apr.

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, whereas 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 in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed 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.

Significance: Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the fi rst validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Pedigrees of families with BRCA1 p.Val1736Ala
A, pedigree of the index family is shown. Circles indicate females and squares indicate males. Slashes indicate death. The proband is indicated by an arrow. Shading in the left lower quadrant indicates ovarian cancer. Shading in the left upper quadrant indicates unilateral breast cancer, and in both left and right upper quadrants, bilateral breast cancer. Shading in the right lower quadrant indicates cancer which is not breast or ovarian. Current ages or age at death, and age at cancer diagnosis are listed below each individual, as is genetic status if known. UNK is unknown. B, a second representative pedigree with the BRCA1 p.Val1736Ala alteration is shown.
Figure 2
Figure 2. Analysis of the BRCA1 p.Val1736Ala Mutation
A, partial sequence alignment of a BRCA1 BRCT domain from different species showing that BRCA1 V1736 and P1749 residues (highlighted in red) are completely conserved across all vertebrate species. Numbers on top of the alignment indicate amino acid positions of the human BRCA1 protein. Conservation below describes sequence conservation (*, identical; :, ≥ 80% conservation; ., ≥ 60% conservation). B, modeling (based on pdb code 1t15) of the interaction between the BRCA1 BRCT domains and a peptide of BACH1. BRCA1 is colored in grey with disease causing mutants of the conserved residues in red. The BACH1 peptide is colored in purple. C, WT BRCA1 (shown as a green focus) but not the p.Val1736Ala or p.Pro1749Arg mutant efficiently colocalized with mcherryLacIFokI fusion endonuclease induced DNA double-strand breaks. D, percentage of cells with BRCA1 (WT or mutant) colocalizing to FokI was quantified. At least 100 cells were assessed for each data point (n > 100). Measurements were obtained in triplicates and reported as means of three replicates. P values were calculated using student t-test, with P < 0.05 for all comparisons. Error bars indicate standard error of the mean (S.E.M). E, Co-immunoprecipitation of Epitope tagged BRCA1 (Myc-BRCA1), WT or mutants from 293T cells at room temperature for 2 hours followed by immunoblot for RAP80.
Figure 3
Figure 3. Re-sequencing of BRCA1 c.2681_2682delAA mutation carrier
A, chromatogram showing the wild-type BRCA1 sequence in lymphocyte DNA from a non-carrier individual. B, chromatogram from lymphocyte DNA showing the heterozygous status of the Scottish woman previously reported as homozygous for the BRCA1 c.2681_2682delAA mutation. Both the mutant and wild-type alleles are clearly present.
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Comment in

References

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