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

Abstract

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.

Using structural analysis in silico to assess the impact of missense variants in MEN1

“…The standards and guidelines published by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) describe a framework for the classification of sequence variants (19). Adjustments to this framework for the interpretation of MEN1 missense variants has been proposed (20). However both agree that variants of uncertain significance should not be used to guide the clinical management of patients.…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…Currently, the majority of Molecular Genetic Laboratories adopt the American College of Medical Genetics and Genomics (ACMG) guidelines to assess variant pathogenicity . These guidelines are intended for the evaluation of penetrant monogenic disorders with well‐established disease‐gene associations and employ a multitiered approach, which considers a number of variant‐ and gene‐specific factors (Table ) . The individual pieces of evidence are then considered in combination, and using predetermined criteria, enable the classification of variant into one of five groups: “benign,” “likely benign,” “uncertain significance,” “likely pathogenic” or “pathogenic” (although these categories are based on estimated probabilities and are not absolute) .…”

“… A recent study has proposed locus‐specific adjustments to the ACMG‐AMP guidelines for missense variants in the MEN1 gene which place additional weight on patient phenotype and family history (Romanet et al, Hum Mut 2019) …”

“…18,71 These guidelines are intended for the evaluation of penetrant monogenic disorders with well-established disease-gene associations and employ a multitiered approach, which considers a number of variant-and gene-specific factors (Table 2). 18,71,72 The individual pieces of evidence are then considered in combination, and using predetermined criteria, enable the classification of variant into one of five groups: "benign," "likely benign," "uncertain significance," "likely pathogenic" or "pathogenic" (although these categories are based on estimated probabilities and are not absolute). 3 Although the ACMG guidelines provide a standardized approach to variant interpretation, there is considerable scope for variability and/or ambiguity in how specific criteria are applied, such that individual users may report different interpretations of the same variant.…”

Data-driven modelling of mutational hotspots and in-silico predictors in hypertrophic cardiomyopathy

“…Eight sarcomeric genes collectively provide firm molecular diagnoses for ~27% of HCM patients, with a further ~13% of patients carrying VUS in the same genes. It has been suggested that disease and genespecific approaches are needed to improve interpretation [16] and guidelines have been produced for specific genes and/or disease areas [17][18][19][20][21]. Missense variant clustering is a gene-specific metric that falls under the ACMG evidence category PM1('mutational hotspot').…”