Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN Study Group

Masson, Emmanuelle, Zou, Wen-Bin, Pu, Na, Rebours, Vinciane, Génin, Emmanuelle, Wu, Hao, Lin, Jin-Huan, Wang, Yuan-Chen, Li, Zhao-Shen, Cooper, David N. ORCID: https://orcid.org/0000-0002-8943-8484, Férec, Claude, Liao, Zhuan and Chen, Jian-Min 2023. Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN Study Group. Pancreatology 23 (5) , pp. 491-506. 10.1016/j.pan.2023.04.004

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Abstract

Background PRSS1 was the first reported chronic pancreatitis (CP) gene. The existence of both gain-of-function (GoF) and gain-of-proteotoxicity (GoP) pathological PRSS1 variants, together with the fact that PRSS1 variants have been identified in CP subtypes spanning the range from monogenic to multifactorial, has made the classification of PRSS1 variants very challenging. Methods All currently reported PRSS1 variants (derived primarily from two databases) were manually reviewed with respect to their clinical genetics, functional analysis and population allele frequency. They were classified by variant type and pathological mechanism within the framework of our recently proposed ACMG/AMP guidelines-based seven-category system. Results The total number of distinct germline PRSS1 variants included for analysis was 100, comprising 3 copy number variants (CNVs), 12 5′ and 3′ variants, 19 intronic variants, 5 nonsense variants, 1 frameshift deletion variant, 6 synonymous variants, 1 in-frame duplication, 3 gene conversions and 50 missense variants. Based upon a combination of clinical genetic and functional analysis, population data and in silico analysis, we classified 26 variants (all 3 CNVs, the in-frame duplication, all 3 gene conversions and 19 missense) as “pathogenic”, 3 variants (missense) as “likely pathogenic”, 5 variants (four missense and one promoter) as “predisposing”, 13 variants (all missense) as “unknown significance”, 2 variants (missense) as “likely benign”, and all remaining 51 variants as “benign”. Conclusions We describe an expert classification of the 100 PRSS1 variants reported to date. The results have immediate implications for reclassifying many ClinVar-registered PRSS1 variants as well as providing optimal guidelines/standards for reporting PRSS1 variants.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2024-07-19
Publisher:	Elsevier
ISSN:	1424-3903
Date of First Compliant Deposit:	26 July 2023
Date of Acceptance:	13 April 2023
Last Modified:	14 Apr 2024 16:37
URI:	https://orca.cardiff.ac.uk/id/eprint/161247

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