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@ARTICLE{Kumar:167140,
      author       = {A. Kumar$^*$ and N. Paramasivam and O. R. Bandapalli$^*$
                      and M. Schlesner$^*$ and T. Chen and R. Sijmons and D.
                      Dymerska and K. Golebiewska and M. Kuswik and J. Lubinski
                      and K. Hemminki$^*$ and A. Försti$^*$},
      title        = {{A} rare large duplication of {MLH}1 identified in {L}ynch
                      syndrome.},
      journal      = {Hereditary cancer in clinical practice},
      volume       = {19},
      number       = {1},
      issn         = {1897-4287},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2021-00161},
      pages        = {10},
      year         = {2021},
      note         = {#EA:C050#LA:B062#},
      abstract     = {The most frequently identified strong cancer predisposition
                      mutations for colorectal cancer (CRC) are those in the
                      mismatch repair (MMR) genes in Lynch syndrome. Laboratory
                      diagnostics include testing tumors for immunohistochemical
                      staining (IHC) of the Lynch syndrome-associated DNA MMR
                      proteins and/or for microsatellite instability (MSI)
                      followed by sequencing or other techniques, such as
                      denaturing high performance liquid chromatography (DHPLC),
                      to identify the mutation.In an ongoing project focusing on
                      finding Mendelian cancer syndromes we applied
                      whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC
                      families.Three families were identified with a
                      pathogenic/likely pathogenic germline variant in a MMR gene
                      that had previously tested negative in DHPLC gene variant
                      screening. All families had a history of CRC in several
                      family members across multiple generations. Tumor analysis
                      showed loss of the MMR protein IHC staining corresponding to
                      the mutated genes, as well as MSI. In family A, a structural
                      variant, a duplication of exons 4 to 13, was identified in
                      MLH1. The duplication was predicted to lead to a frameshift
                      at amino acid 520 and a premature stop codon at amino acid
                      539. In family B, a 1 base pair deletion was found in MLH1,
                      resulting in a frameshift and a stop codon at amino acid
                      491. In family C, we identified a splice site variant in
                      MSH2, which was predicted to lead loss of a splice donor
                      site.We identified altogether three pathogenic/likely
                      pathogenic variants in the MMR genes in three of the 19
                      sequenced families. The MLH1 variants, a duplication of
                      exons 4 to 13 and a frameshift variant, were novel, based on
                      the InSiGHT and ClinVar databases; the MSH2 splice site
                      variant was reported by a single submitter in ClinVar. As a
                      variant class, duplications have rarely been reported in the
                      MMR gene literature, particularly those covering several
                      exons.},
      keywords     = {Genetic predisposition (Other) / Lynch syndrome (Other) /
                      Mismatch repair genes (Other) / Whole-genome sequencing
                      (Other)},
      cin          = {C050 / B062 / HD01 / B240},
      ddc          = {610},
      cid          = {I:(DE-He78)C050-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)HD01-20160331 / I:(DE-He78)B240-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33468175},
      doi          = {10.1186/s13053-021-00167-0},
      url          = {https://inrepo02.dkfz.de/record/167140},
}