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Hum Mutat. 2019 Jun;40(6):661-674. doi: 10.1002/humu.23746. Epub 2019 Mar 28.

Proposition of adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants.

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Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology Hospital La Conception, Marseille, France.
CHU Lille, Service de Biochimie et Biologie moléculaire "Hormonologie, Métabolisme-Nutrition, Oncologie", F-59037 Lille, France.
Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, 27 Rue du Faubourg Saint Jacques, Paris, France.
Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, F-59000 Lille, France.
Laboratory of Molecular Biology, Hospital La Conception, Marseille, France.
Department of Endocrine Surgery, University Hospital of Dijon, and INSERM, U866, Epidemiology and Clinical Research in Digestive Oncology Team, and INSERM, CIC1432, Clinical Epidemiology Unit, University Hospital of Dijon, Clinical Investigation Center, Clinical Epidemiology/Clinical Trials Unit, Dijon, France.
Hospices Civils de Lyon, Fédération d'Endocrinologie, Université Claude Bernard Lyon 1, HESPER EA 7425, F-69008, Lyon, France.
Genetics Department, Hospices Civils de LYON (HCL), University Hospital, East Pathology Center, B-A3, 59 Bld Pinel, 69677, Bron Cedex, France.
Aix Marseille Univ, APHM, INSERM, MMG, Département de Génétique CHU La Timone Enfants, Marseille, France.


In 2015, the ACMG-AMP guidelines provided a general procedure for the objective and reproducible classification of genomic variants. While the benefits of this framework are of major importance, its adaptation for locus-specific use is needed. Multiple Endocrine Neoplasia type 1 (MEN1) occurs due to inactivating mutations in the tumour suppressor gene MEN1, including 20% of missense variants. The classification of these variants may be extremely challenging. Here, we compared the interpretation of the 122 MEN1 missense variants, identified in the French population over the past 15 years by the TENGEN network (French oncogenetics network of neuroendocrine tumors) versus by using the ACMG-AMP guidelines, and analyzed the causes of discordance. A total of 59.8% of missense variants were termed as (likely)-pathogenic variants by TENGEN versus only 28.7% using ACMG-AMP guidelines. Actually, 53.4% (39/73) of TENGEN (likely)-pathogenic variants were declassified in variant of uncertain significance (VUS) by using ACMG-AMP guidelines, thereby affecting the clinical management of patients and their families. Twenty of these ACMG-AMP VUS were found in patients with a clinically authentic MEN1 disease. Here, TENGEN proposes adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants. These propositions merge both the classification systems, and are particularly interesting, as MEN1 is included in the ACMG secondary findings list for reporting in clinical genomic sequencing.


ACMG-AMP guidelines, genetic testing, MEN1, missense variants, pathogenicity classification, sequence variation


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