Academic Journal
View in EDS

Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

Bibliographic Details
Title: Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant
Authors: Ines Block, Àngels Mateu-Regué, Thi Tuyet Nhu Do, Ieva Miceikaite, Daniel Sdogati, Martin J. Larsen, Qin Hao, Henriette Roed Nielsen, Susanne E. Boonen, Anne-Bine Skytte, Uffe Birk Jensen, Louise K. Høffding, Arcangela De Nicolo, Alessandra Viel, Emma Tudini, Michael T. Parsons, Thomas V. O. Hansen, Maria Rossing, Torben A. Kruse, Amanda B. Spurdle, Mads Thomassen
Source: Breast Cancer Research, Vol 26, Iss 1, Pp 1-14 (2024)
Publisher Information: BMC, 2024.
Publication Year: 2024
Collection: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Subject Terms: BRCA1, Dual carrier, Fanconi Anemia, Variant classification, Exon duplication, Transcription activation domain assay, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
More Details: Abstract 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1465-542X
Relation: https://doaj.org/toc/1465-542X
DOI: 10.1186/s13058-023-01755-9
Access URL: https://doaj.org/article/7555813f6f454c71871a5c318d759708
Accession Number: edsdoj.7555813f6f454c71871a5c318d759708
Database: Directory of Open Access Journals
FullText Text:
  Availability: 0
CustomLinks:
  – Url: https://resolver.ebsco.com/c/xy5jbn/result?sid=EBSCO:edsdoj&genre=article&issn=1465542X&ISBN=&volume=26&issue=1&date=20240101&spage=1&pages=1-14&title=Breast Cancer Research&atitle=Male%20with%20an%20apparently%20normal%20phenotype%20carrying%20a%20BRCA1%20exon%2020%20duplication%20in%20trans%20to%20a%20BRCA1%20frameshift%20variant&aulast=Ines%20Block&id=DOI:10.1186/s13058-023-01755-9
    Name: Full Text Finder (for New FTF UI) (s8985755)
    Category: fullText
    Text: Find It @ SCU Libraries
    MouseOverText: Find It @ SCU Libraries
  – Url: https://doaj.org/article/7555813f6f454c71871a5c318d759708
    Name: EDS - DOAJ (s8985755)
    Category: fullText
    Text: View record from DOAJ
    MouseOverText: View record from DOAJ
Header DbId: edsdoj
DbLabel: Directory of Open Access Journals
An: edsdoj.7555813f6f454c71871a5c318d759708
RelevancyScore: 1020
AccessLevel: 3
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 1020.37725830078
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Ines+Block%22">Ines Block</searchLink><br /><searchLink fieldCode="AR" term="%22Àngels+Mateu-Regué%22">Àngels Mateu-Regué</searchLink><br /><searchLink fieldCode="AR" term="%22Thi+Tuyet+Nhu+Do%22">Thi Tuyet Nhu Do</searchLink><br /><searchLink fieldCode="AR" term="%22Ieva+Miceikaite%22">Ieva Miceikaite</searchLink><br /><searchLink fieldCode="AR" term="%22Daniel+Sdogati%22">Daniel Sdogati</searchLink><br /><searchLink fieldCode="AR" term="%22Martin+J%2E+Larsen%22">Martin J. Larsen</searchLink><br /><searchLink fieldCode="AR" term="%22Qin+Hao%22">Qin Hao</searchLink><br /><searchLink fieldCode="AR" term="%22Henriette+Roed+Nielsen%22">Henriette Roed Nielsen</searchLink><br /><searchLink fieldCode="AR" term="%22Susanne+E%2E+Boonen%22">Susanne E. Boonen</searchLink><br /><searchLink fieldCode="AR" term="%22Anne-Bine+Skytte%22">Anne-Bine Skytte</searchLink><br /><searchLink fieldCode="AR" term="%22Uffe+Birk+Jensen%22">Uffe Birk Jensen</searchLink><br /><searchLink fieldCode="AR" term="%22Louise+K%2E+Høffding%22">Louise K. Høffding</searchLink><br /><searchLink fieldCode="AR" term="%22Arcangela+De+Nicolo%22">Arcangela De Nicolo</searchLink><br /><searchLink fieldCode="AR" term="%22Alessandra+Viel%22">Alessandra Viel</searchLink><br /><searchLink fieldCode="AR" term="%22Emma+Tudini%22">Emma Tudini</searchLink><br /><searchLink fieldCode="AR" term="%22Michael+T%2E+Parsons%22">Michael T. Parsons</searchLink><br /><searchLink fieldCode="AR" term="%22Thomas+V%2E+O%2E+Hansen%22">Thomas V. O. Hansen</searchLink><br /><searchLink fieldCode="AR" term="%22Maria+Rossing%22">Maria Rossing</searchLink><br /><searchLink fieldCode="AR" term="%22Torben+A%2E+Kruse%22">Torben A. Kruse</searchLink><br /><searchLink fieldCode="AR" term="%22Amanda+B%2E+Spurdle%22">Amanda B. Spurdle</searchLink><br /><searchLink fieldCode="AR" term="%22Mads+Thomassen%22">Mads Thomassen</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: Breast Cancer Research, Vol 26, Iss 1, Pp 1-14 (2024)
– Name: Publisher
  Label: Publisher Information
  Group: PubInfo
  Data: BMC, 2024.
– Name: DatePubCY
  Label: Publication Year
  Group: Date
  Data: 2024
– Name: Subset
  Label: Collection
  Group: HoldingsInfo
  Data: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22BRCA1%22">BRCA1</searchLink><br /><searchLink fieldCode="DE" term="%22Dual+carrier%22">Dual carrier</searchLink><br /><searchLink fieldCode="DE" term="%22Fanconi+Anemia%22">Fanconi Anemia</searchLink><br /><searchLink fieldCode="DE" term="%22Variant+classification%22">Variant classification</searchLink><br /><searchLink fieldCode="DE" term="%22Exon+duplication%22">Exon duplication</searchLink><br /><searchLink fieldCode="DE" term="%22Transcription+activation+domain+assay%22">Transcription activation domain assay</searchLink><br /><searchLink fieldCode="DE" term="%22Neoplasms%2E+Tumors%2E+Oncology%2E+Including+cancer+and+carcinogens%22">Neoplasms. Tumors. Oncology. Including cancer and carcinogens</searchLink><br /><searchLink fieldCode="DE" term="%22RC254-282%22">RC254-282</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Abstract 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.
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: article
– Name: Format
  Label: File Description
  Group: SrcInfo
  Data: electronic resource
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 1465-542X
– Name: NoteTitleSource
  Label: Relation
  Group: SrcInfo
  Data: https://doaj.org/toc/1465-542X
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1186/s13058-023-01755-9
– Name: URL
  Label: Access URL
  Group: URL
  Data: <link linkTarget="URL" linkTerm="https://doaj.org/article/7555813f6f454c71871a5c318d759708" linkWindow="_blank">https://doaj.org/article/7555813f6f454c71871a5c318d759708</link>
– Name: AN
  Label: Accession Number
  Group: ID
  Data: edsdoj.7555813f6f454c71871a5c318d759708
PLink https://login.libproxy.scu.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsdoj&AN=edsdoj.7555813f6f454c71871a5c318d759708
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1186/s13058-023-01755-9
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 14
        StartPage: 1
    Subjects:
      – SubjectFull: BRCA1
        Type: general
      – SubjectFull: Dual carrier
        Type: general
      – SubjectFull: Fanconi Anemia
        Type: general
      – SubjectFull: Variant classification
        Type: general
      – SubjectFull: Exon duplication
        Type: general
      – SubjectFull: Transcription activation domain assay
        Type: general
      – SubjectFull: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
        Type: general
      – SubjectFull: RC254-282
        Type: general
    Titles:
      – TitleFull: Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Ines Block
      – PersonEntity:
          Name:
            NameFull: Àngels Mateu-Regué
      – PersonEntity:
          Name:
            NameFull: Thi Tuyet Nhu Do
      – PersonEntity:
          Name:
            NameFull: Ieva Miceikaite
      – PersonEntity:
          Name:
            NameFull: Daniel Sdogati
      – PersonEntity:
          Name:
            NameFull: Martin J. Larsen
      – PersonEntity:
          Name:
            NameFull: Qin Hao
      – PersonEntity:
          Name:
            NameFull: Henriette Roed Nielsen
      – PersonEntity:
          Name:
            NameFull: Susanne E. Boonen
      – PersonEntity:
          Name:
            NameFull: Anne-Bine Skytte
      – PersonEntity:
          Name:
            NameFull: Uffe Birk Jensen
      – PersonEntity:
          Name:
            NameFull: Louise K. Høffding
      – PersonEntity:
          Name:
            NameFull: Arcangela De Nicolo
      – PersonEntity:
          Name:
            NameFull: Alessandra Viel
      – PersonEntity:
          Name:
            NameFull: Emma Tudini
      – PersonEntity:
          Name:
            NameFull: Michael T. Parsons
      – PersonEntity:
          Name:
            NameFull: Thomas V. O. Hansen
      – PersonEntity:
          Name:
            NameFull: Maria Rossing
      – PersonEntity:
          Name:
            NameFull: Torben A. Kruse
      – PersonEntity:
          Name:
            NameFull: Amanda B. Spurdle
      – PersonEntity:
          Name:
            NameFull: Mads Thomassen
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 01
              Type: published
              Y: 2024
          Identifiers:
            – Type: issn-print
              Value: 1465542X
          Numbering:
            – Type: volume
              Value: 26
            – Type: issue
              Value: 1
          Titles:
            – TitleFull: Breast Cancer Research
              Type: main
ResultId 1