UMD-MEN1 Database: An Overview of the 370 MEN1 Variants Present in 1676 Patients From the French Population

Abstract

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the MEN1 gene characterized by a broad spectrum of clinical manifestations, of which the most frequent are primary hyperparathyroidism, pituitary adenomas, and neuroendocrine tumors. Objective The aim of this work was to facilitate interpretation of variants and improve the genetic counseling and medical care of families of patients with MEN1. Design, Setting, and Patients The TENGEN network (Oncogenetics Network of Neuroendocrine Tumors) has interpreted and collected all allelic variants and clinical characteristics of the MEN1-positive patients identified through genetic testing performed in the French population from 1997 to 2015. Patients and their variants were registered in the locus-specific UMD-MEN1 database (www.umd.be/MEN1/). Main Outcomes Variant classification, age-related penetrance, and odds ratios. Results A total of 370 distinct variants reported in 1676 patients, including 181 unpublished variants, have been registered. This database analysis revealed a low frequency (6.6%) of benign or likely benign missense variants in MEN1. Eight families (1.9%) had members with familial isolated hyperparathyroidism and harbored the same mutations as that found in families with authentic MEN1. An association existed between large rearrangements and an earlier onset of the disease, whereas no difference was observed between truncating and nontruncating variants. Conclusion The UMD-MEN1 database provides an exhaustive overview of the MEN1 variants present in the French population. For each variant, a classification is publicly available. Clinical data collections allow the determination of genotype-phenotype correlation and age-related penetrance of lesions in the cohort.

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

“…(Lemos & Thakker, 2008;Romanet et al, 2018). To date, no mutational hot spot has been defined, but some recurrent mutations have been described (Lemos & Thakker, 2008;Romanet et al, 2018;Thakker, 2014;Thevenon et al, 2013Thevenon et al, , 2015 4.3.5 | Criterion PP2: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease In our series, we observed that the rate of BV or LBV was very low when using any of the classification processes (Figure 1). It is well established that among the few MEN1 BVs with a frequency superior to 1% in the general population, only two are missense variants (c.512 G > A, p.(Arg171Gln), and c.1621G > A; p.(Ala541Thr); Thakker, 2010).…”

“…Disease‐causing variant can occur throughout the entire sequence of the MEN1 gene (Lemos & Thakker, ; Romanet et al, ). To date, no mutational hot spot has been defined, but some recurrent mutations have been described (Lemos & Thakker, ; Romanet et al, ; Thakker, ; Thevenon et al, , ). The genotype‐phenotype relationship remains under debate.…”

“…Only six MEN1 variants in the coding sequence and intron‐exon junctions were previously reported as polymorphisms (Romanet et al, ; Thakker, ). The minimal allele frequency of these MEN1 polymorphisms was 0.76% in gnomAD v2.1; therefore, we propose this threshold for allele frequency in the BA1 criterion.…”

“…| 671 contribution, and 17.1% for the disease penetrance at 20 years (Romanet et al, 2018), given a "maximum credible population allele frequency" at 7.84 × 10 −5 using the App available at http://cardiodb. (meningioma, lipoma…).…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…As such, the penetrance estimates above are intended to be illustrative. References relevant to specific genes include AIP 19,42 ; CDC73 123,124 ; MEN1 26,125 ; SDH complex genes 11,12,120,121 ; PRKAR1A 28 ; RET 23,24,126 ; and VHL. 127 Penetrance estimates for MEN4 due to CDKN1B mutations are not available due to low numbers of reported cases.…”