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Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies

Thomas McKerrell, Thaidy Moreno, Hannes Ponstingl, Niccolo Bolli, João M. L. Dias, German Tischler, Vincenza Colonna, Bridget Manasse, Anthony Bench, David Bloxham, Bram Herman, Danielle Fletcher, Naomi Park, Michael A. Quail, Nicla Manes, Clare Hodkinson, Joanna Baxter, Jorge Sierra, Theodora Foukaneli, Alan J. Warren, Jianxiang Chi, Paul Costeas, Roland Rad, Brian Huntly, Carolyn Grove, Zemin Ning, Chris Tyler-Smith, Ignacio Varela, Mike Scott, Josep Nomdedeu, Ville Mustonen and George S. Vassiliou

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  • RE: Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies
    • George Vassiliou, Wellcome Truats Senior Fellow in Clinical Science Wellcome Trust Sanger Institute
    • Other Contributors:
      • Thomas McKerrell, Wellcome Trust Clinical Research Training Fellow

    We thank Yannakou et al for their comment and agree that the insertion of a guanine at position c.1927 and the duplication of a guanine at position c.1934 of ASXL1 are equivalent changes. After consulting with our associate editor, we have now clarified this in our manuscript proofs.

    Conflict of Interest:
    None declared.
  • RE: Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies
    • Costas Kleanthes Yannakou, Haematology Fellow Peter MacCallum Cancer Centre
    • Other Contributors:
      • Kate Jones, Medical Scientist
      • Georgina Ryland, Haematology Fellow
      • Christopher McEvoy, Medical Scientist
      • Michelle McBean, Medical Scientist
      • Piers Blombery, Consultant Haematologist

    McKerrell et al.1 report that 6 of the 11 ASXL1 mutations detected in their cohort of 50 MDS samples were frame-shift mutations at ASXL1 c.1927 due to an insertion of a guanine resulting in p.G643fs*15. The authors hypothesise that despite not detecting this mutation in 40 samples from patients without evidence of a clonal blood disorder it may represent a sequencing artefact. A case has been made that the c.1934dup is not a somatic variant but rather represents a sequencing error due to the guanine homopolymer that extends from c.1927 to c.19342.

    The insertion of a guanine at position c.1927 and the duplication of a guanine at position c.1934 are equivalent changes, both resulting in the extension of the guanine homopolymer from 8 to 9 base pairs in length. Likewise, the protein change described by the authors (p.G643fs*15) is equivalent to that attributed to the c.1934dup (p.G646Wfs*12).

    The Human Genome Variation Society Recommendations for the Description of Sequence variants: 2016 Update reiterates the convention that when different possible descriptions can be applied to a variant, as sometimes occurs in stretches of repeated DNA sequence, the most 3’ position possible is arbitrarily deemed to be changed3. In addition, when a variant is able to be described as either a duplication or an insertion, the duplication nomenclature is recommended.

    We therefore conclude that the ASXL1 c.1934dup mutation was detected within 6 of the 50 MDS sampl...

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    Conflict of Interest:
    None declared.