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NGS mismapping confounds the clinical interpretation of the PRSS1 p.Ala16Val (c.47C>T) variant in chronic pancreatitis
  1. Emmanuelle Génin1,2,
  2. David N Cooper3,
  3. Emmanuelle Masson1,2,
  4. Claude Férec1,2,
  5. Jian-Min Chen1
  1. 1Inserm, Univ Brest, EFS, UMR 1078, GGB, Brest, France
  2. 2Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, Brest, France
  3. 3Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
  1. Correspondence to Dr Jian-Min Chen, INSERM U1078 – EFS – UBO, 22 avenue Camille Desmoulins, 29218 Brest, France; jian-min.chen{at}univ-brest.fr

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We read with interest the recent publication by Weiss and colleagues, which addressed the pitfalls of using next-generation sequencing (NGS) to diagnose PRSS1 variants in chronic pancreatitis (CP).1 Specifically, having failed to authenticate an NGS-identified ‘PRSS1 c.47C>T (p.Ala16Val) variant’ by Sanger sequencing the PRSS1 gene in the supposed carrier, they postulated that this artefact could have arisen from sequence reads emanating from one of PRSS1’ highly homologous and closely linked (7q34) pseudogenes, PRSS3P2. Herein, we address another NGS-related pitfall that contributes to confusion in relation to the clinical interpretation of PRSS1 p.Ala16Val.

p.Ala16Val is the third most commonly detected rare PRSS1 variant in CP; its putative pathological involvement is supported by its ability to increase trypsinogen autoactivation.2 ClinVar, however, ascribes to it conflicting interpretations of pathogenicity (ie, likely benign (1); pathogenic (3) and uncertain significance (2)).3 The main reason for this appears to be its relatively high allele frequency (ie, 0.006607) in all gnomAD V.2.1.1 …

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Footnotes

  • Contributors EG performed the bioinformatics analysis and revised the paper. DNC, EM and CF contributed to data interpretation and revised the paper. J-MC conceived the study, performed the meta-analysis and drafted the paper. All authors approved the final manuscript.

  • Funding This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), France.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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