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@ARTICLE{Rashid:303442,
      author       = {M. U. Rashid and N. Muhammad and S. Arif and H. Naeemi and
                      U. Hamann$^*$},
      title        = {{G}enetic landscape of {P}akistani familial breast cancer
                      patients using multigene panel testing.},
      journal      = {International journal of cancer},
      volume       = {nn},
      issn         = {0020-7136},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2025-01655},
      pages        = {nn},
      year         = {2025},
      note         = {#LA:B072# / epub},
      abstract     = {Pathogenic/likely pathogenic (P/LP) variants in high-,
                      moderate-, and low-penetrance genes account for
                      approximately half of all familial breast cancer (BC) cases.
                      In Pakistan, data on P/LP variants beyond BRCA1/2 remain
                      limited. This study investigated the frequency and
                      distribution of P/LP variants in Pakistani familial BC
                      patients using a 14-gene hereditary breast and ovarian
                      cancer (HBOC) core panel. A total of 160 familial BC
                      patients previously tested negative for protein-truncating
                      variants in BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and
                      TP53 using conventional methods were included.
                      Next-generation sequencing (NGS) was performed using the
                      Illumina MiSeq platform, and all identified P/LP variants
                      were validated by Sanger sequencing. Twenty-four unique P/LP
                      variants were identified across seven genes: BRCA1 (n = 10),
                      BRCA2 (n = 6), TP53 (n = 3), CHEK2 (n = 2), PALB2, ATM, and
                      RAD51C (n = 1 each). Two recurrent BRCA1 variants,
                      p.Gln169Ter and p.Val757Phefs*8, were identified in three
                      patients each. NGS-detected P/LP variants were identified in
                      $18.1\%$ (29/160) of patients. When combined with previous
                      germline testing in the same cohort, the overall detection
                      rate increased to $50.2\%$ (132/263): BRCA1 (101/263;
                      $38.4\%),$ BRCA2 (22/263; $8.4\%),$ TP53 (3/263; $1.1\%),$
                      CHEK2 (2/263; $0.8\%),$ PALB2 (2/263; $0.8\%),$ ATM (1/263;
                      $0.4\%)$ and RAD51C (1/263; $0.4\%).$ Among these, BRCA1/2
                      variants accounted for $93.2\%$ (123/132) of all P/LP
                      variants. Our findings demonstrate that P/LP variants are
                      concentrated in a limited number of genes, with BRCA1/2 as
                      the predominant contributors. We propose a cost-effective,
                      first-tier genetic testing panel comprising seven genes
                      (ATM, BRCA1, BRCA2, CHEK2, RAD51C, PALB2, and TP53) for
                      familial BC risk assessment in Pakistan.},
      keywords     = {Pakistan (Other) / familial breast cancer (Other) /
                      next‐generation sequencing (Other) / pathogenic variants
                      (Other)},
      cin          = {B072},
      ddc          = {610},
      cid          = {I:(DE-He78)B072-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40749126},
      doi          = {10.1002/ijc.70070},
      url          = {https://inrepo02.dkfz.de/record/303442},
}