NGS mismapping confounds the clinical interpretation of the PRSS1 p.Ala16Val (c.47C>T) variant in chronic pancreatitis.

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 …