TPS1600 Background: Rare cancers is defined as fewer than 15 cases per 100,000 people per year and account for 27% cancers diagnosed and lead to 25% of cancer-related deaths. Nearly 13% (1 in 8) of all cancers diagnosed in adults ages 20 and older are rare. All pediatric cancers are rare and approximately 12,600 children under the age of 20 years are diagnosed with cancer each year. Rarity of these diseases has caused a stagnation in understanding the tumor biology and developing newer therapies. Initiatives like Orphan Drug Act (1983) and Rare Disease Act (2002) has led to improvement in funding and research about these rare tumors. The Cancer Moonshot Research Initiative funded My Pediatric and Adult Rare Tumor (MyPART) network (cancer.gov/mypart) in the NCI Pediatric Oncology Branch and launched a longitudinal Natural History Study for Children and Adults with Rare Solid Tumors (NCT03739827). Methods: A prospective study to evaluate the natural history of rare pediatric and adult solid tumors comprehensively and longitudinally. Patients of any age with a rare solid tumor (<15 cases per 100,000 people per year) are eligible. Patients with germline mutation who are at risk of developing these tumors or relatives of participants are also eligible. Patients can participate from home or are are invited to NIH for annual evaluations. Participants complete individual medical history, family history, patient related-outcomes measurements (PROs) and provide samples (blood, saliva) for DNA analysis. Tumors are analyzed using a 500+ gene panel (TruSight500, Illumina Panel) and undergo a comprehensive genomic and epigenomic analysis. Participants invited to NIH undergo a clinical evaluation, genetic counseling, blood collection (standard clinical labs, germline DNA/RNA, immune phenotypes, cytokines, exosomes), and imaging studies, as indicated. The goals of this study are to 1) Estimate and define the clinical spectrum of rare cancers 2) Evaluate and follow biological relatives of patients with rare tumors or carriers of germline genetic variants that predispose to development of rare tumors 3) Develop a better understanding of these diseases in an effort to develop a) Novel therapeutic interventions, b) Preventive/screening guidelines, c) Endpoints for future clinical trials, and d) Relevant patient reported outcomes that can improve our understanding of patients psychosocial and functional needs. Subprotocols under this protocol for children and adults include adrenocortical cancer (NCT04447014), neuroendocrine neoplasms (NCT04488263) and Chordoma (NCT0391046) to gather tumor specific data. Study accrual is ongoing. Clinical trial information: NCT03739827.