Prevalence, tumor characteristics, and clinical impact of <i>LZTR1</i> pathogenic variants in a large, pan-cancer cohort.

10621 Background: Heterozygous germline pathogenic/likely pathogenic (P/LP) loss-of-function (LOF) variants in LZTR1 are associated with hereditary schwannomatosis. To date, the prevalence and penetrance remain poorly defined, and there are currently no well-established surveillance guidelines for individuals with incidental LZTR1 P/LP variants. We sought to describe the prevalence of LZTR1 P/LP variants in a large pan-cancer cohort, characterize the tumor genomic profile of patients with these variants, and report the clinical utility of surveillance imaging in asymptomatic carriers diagnosed incidentally. Methods: Patients with germline P/LP variants in LZTR1 were identified from pan-cancer patients who prospectively enrolled in an institutional review board-approved protocol of matched tumor-normal DNA sequencing (MSK-IMPACT). Clinical and tumor characteristics of LZTR1 carriers were collected from electronic medical records. Results: Among 50,537 patients who underwent germline genetic testing via MSK-IMPACT, 157 (0.31%) were found to harbor a heterozygous germline P/LP variant in LZTR1 . Eight patients presented with a schwannoma diagnosis at the time of genetic testing with an additional three reporting a prior history of schwannoma, for a total of 11 (7.01%) meeting criteria for LZTR1-associated schwannomatosis. In the remaining 146 (93%) of patients, the germline LZTR1 P/LP variant was an incidental finding. The most common cancer types in those identified incidentally included prostate (23), breast (22), colorectal (21), sarcoma (14), and uterine (9). Of the 6 schwannomas with tumor data available, all exhibited a second somatic mutation in the NF2 gene, and 5 displayed loss of heterozygosity of the LZTR1 locus in the tumor favoring the mutant allele. LOH data was available for 117 non-schwannoma tumors. Of these, 33 (28.2%) were found to have LOH favoring the mutant LZTR1 allele. Of patients diagnosed incidentally, 29 underwent MRI of the brain and total spine after detection of the LZTR1 P/LP variant for schwannoma screening. An additional 104 patients underwent whole body imaging (PET/CT or CT chest, abdomen, and pelvis) for cancer surveillance. All patients were asymptomatic and did not have clinical evidence of schwannomatosis on history or physical exam. Of these 133 asymptomatic LZTR1 carriers, no (0%) schwannomas were identified. Conclusions: The prevalence of LZTR1 P/LP variants was 0.3% in an unselected pan-cancer population with &lt; 10% meeting criteria for LZTR1 -associated schwannomatosis, suggesting low penetrance. Imaging performed after variant detection did not identify previously unrecognized disease, suggesting limited clinical utility of routine surveillance in asymptomatic carriers without supportive clinical features. These findings support a more selective, risk-informed approach to management of incidental LZTR1 variants.