Grant Number:	1U24NS131158-01A1 Interpret this number
Primary Investigator:	Plotkin, Scott
Organization:	Massachusetts General Hospital
Project Title:	Neurofibromatosis and Schwannomatosis Genes Variant Curation Expert Panel (VCEP)
Fiscal Year:	2024

ABSTRACT The goal of the Neurofibromatosis (NF) and Schwannomatosis (SWN) Genes Variant Curation Expert Panel (VCEP) is to develop, apply, and disseminate variant curation guidelines for genes associated with neurofibromatosis type 1 (NF1), Legius syndrome (LS), and schwannomatosis (SWN), including NF2-related schwannomatosis (NF2-SWN, formerly known as neurofibromatosis 2) and non-NF2-related schwannomatosis (non-NF2-SWN). NIH has prioritized identifying genetic variants associated with neurological disease and inherited susceptibility to cancer and determining their clinical significance for diagnosis and treatment. NF1 is caused by pathogenic variants (PV) in NF1 whereas LS is caused by PV in SPRED1. SWN is caused by PV in NF2, SMARCB1 and LZTR1. Patients affected by these neurogenetic tumor suppressor syndromes are commonly managed together in specialized clinics that provide comprehensive care. Historically, these syndromes have been diagnosed clinically, but new international guidelines recommend the use of genetic testing to assist diagnosis. In cancer patients, multigene panels may identify germline variants in NF1, NF2, SPRED1, SMARCB1, and LZTR1 that are pathogenic, likely pathogenic, or of uncertain significance (VUS) in persons who may not exhibit clinical features of NF or SWN. Improved variant classification will foster earlier and more accurate diagnosis and improve treatment for these conditions. A key goal of the VCEP, is to standardize intepretation of variants in these cancer genes and to reduce the number of VUS. Currently, there are no gene-specific guidelines for curation of variants associated with NF1, LS, and SWN and no comprehensive database for these variants. In late 2021, 43 international experts from 14 countries launched an NF/SWN VCEP. ClinGen has provided Step 2 approval for the VCEP to develop gene-specific rules for NF1. Funding will allow the VCEP to test proposed rules for NF1 and to create variant curation rules for NF2 (one of the 73 ACMG Secondary Findings Genes), SMARCB1, LZTR1, and SPRED1. Our approach is to focus on standardization, not innovation. The Specific Aims of the propsal are to: 1. Develop gene-specific guidelines for curation of genes associated with NF1, LS, and SWN with the guidance of rigorous, established, and standardized ClinGen processes and procedures. 2. Curate a wide array of simple and challenging variants to ensure that the guidelines developed are able to classify known pathogenic and benign variants while reducing the number of VUS. 3. Reclassify variants curently in the literature and public databases (LOVD and ClinVar) and deposit them in ClinVar, making them available to the international community and testing laboratories. 4. Disseminate these guidelines by publishing them in peer-reviewed journals, thereby making them freely available for members of the NF community, academic laboratires, and commercial laboratories. This project will standardize curation among academic and commercial labs, will improve the diagnosis and treatment of patients, and will increase the number of curated variants in ClinVar. page 1





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