Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant
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Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant. / Block, Ines; Mateu-Regué, Àngels; Do, Thi Tuyet Nhu; Miceikaite, Ieva; Sdogati, Daniel; Larsen, Martin J.; Hao, Qin; Nielsen, Henriette Roed; Boonen, Susanne E.; Skytte, Anne Bine; Jensen, Uffe Birk; Høffding, Louise K.; De Nicolo, Arcangela; Viel, Alessandra; Tudini, Emma; Parsons, Michael T.; Hansen, Thomas V.O.; Rossing, Maria; Kruse, Torben A.; Spurdle, Amanda B.; Thomassen, Mads.
In: Breast Cancer Research, Vol. 26, No. 1, 6, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant
AU - Block, Ines
AU - Mateu-Regué, Àngels
AU - Do, Thi Tuyet Nhu
AU - Miceikaite, Ieva
AU - Sdogati, Daniel
AU - Larsen, Martin J.
AU - Hao, Qin
AU - Nielsen, Henriette Roed
AU - Boonen, Susanne E.
AU - Skytte, Anne Bine
AU - Jensen, Uffe Birk
AU - Høffding, Louise K.
AU - De Nicolo, Arcangela
AU - Viel, Alessandra
AU - Tudini, Emma
AU - Parsons, Michael T.
AU - Hansen, Thomas V.O.
AU - Rossing, Maria
AU - Kruse, Torben A.
AU - Spurdle, Amanda B.
AU - Thomassen, Mads
N1 - Publisher Copyright: © 2024, The Author(s).
PY - 2024
Y1 - 2024
N2 - Background: Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype. Methods: We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells. Results: Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability. Conclusions: This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.
AB - Background: Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype. Methods: We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells. Results: Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability. Conclusions: This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.
KW - BRCA1
KW - Dual carrier
KW - Exon duplication
KW - Fanconi Anemia
KW - Transcription activation domain assay
KW - Variant classification
U2 - 10.1186/s13058-023-01755-9
DO - 10.1186/s13058-023-01755-9
M3 - Journal article
C2 - 38195559
AN - SCOPUS:85181753466
VL - 26
JO - Breast Cancer Research
JF - Breast Cancer Research
SN - 1465-5411
IS - 1
M1 - 6
ER -
ID: 379655683