Journal
HUMAN MUTATION
Volume 43, Issue 7, Pages 919-927Publisher
WILEY
DOI: 10.1002/humu.24376
Keywords
ACMG; loss-of-function; LZTR1; schwannomatosis; variant classification
Categories
Funding
- Manchester National Institute for Health Research (NIHR) Biomedical Research Centre [IS-BRC-1215-20007]
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Schwannomatosis is a rare tumor predisposition syndrome that is difficult to classify and interpret the clinical significance of novel variants. Current classification guidelines can accurately identify most pathogenic variants, but there is a high frequency of LoF LZTR1 variants in the general population, making classification of novel variants challenging.
Schwannomatosis is a rare tumor predisposition syndrome that causes multiple schwannomas. Germline loss-of-function (LoF) LZTR1 variants were only recently identified as disease-causing, so relatively few variants have been identified in patients. In addition, many LoF variants exist in Genome Aggregation Database (gnomAD) in people who do not have clinical symptoms of schwannomatosis. These factors, and the incomplete penetrance seen in this condition, hinder definitive interpretation of the clinical significance of novel LoF variants identified in schwannomatosis patients. We collated published LOF LZTR1 variants identified in schwannomatosis patients and classified them according to current American College of Medical Genetics and Genomics/Association for Molecular Pathology/Association of Clinical Genomic Science guidelines. Subsequently, pathogenic/likely pathogenic schwannomatosis-associated LoF variants were compared with LoF LZTR1 variants reported in gnomAD data. Using current classification guidelines, 64/71 LoF LZTR1 variants reported in schwannomatosis patients in the literature were classified as pathogenic/likely pathogenic, and their frequency in probands 64/359 (17.8%) was significantly higher than the frequency of potential LoF variants identified in the general population (0.36%; p < 0.0001). The majority of published classifications of schwannomatosis-associated LoF variants are robust. However, the high frequency of LoF LZTR1 variants in the general population suggests that LZTR1 variants confer a reduced risk of schwannomas compared to germline NF2 and SMARCB1 pathogenic variants, making classification of novel variants challenging.
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