Abstract Background: Rare tumors are defined as <15 cases/100,000 people/year and present an unmet need due to lack of effective medical treatments, paucity of biospecimens and research models, and difficulty accruing to clinical trials. MyPART (My Pediatric and Adult Rare Tumor Network) was established to: 1) engage patients/advocates as partners in rare tumor research, 2) provide expertise and personalized health care to children and young adults with rare tumors, and 3) build databases and tools to advance research on new treatments for rare tumors. We have developed a natural history and biospecimen acquisition study (NCT03739827), enrolling patients with rare solid tumors, their family members, and participants with germline mutations at increased rare tumor risk. Method: Participants in our natural history study enroll remotely or come to the National Institutes of Health Clinical Center. Participants complete medical and family history forms, patient reported outcomes (PROs), and provide tumor samples and blood and/or saliva for DNA/RNA analysis. For patients coming to the Clinical Center, blood samples are collected for immune phenotyping and cytokine analysis. Clinical staff extract medical records for downstream analyses. Tumors are analyzed using a 500+ gene panel and genomic analysis. Participants are followed yearly to collect data on recurrence, progression, PROs, development of additional tumors, and response to treatments such as standard of care and any treatment trials they may join. Results: We report a clinical and molecular summary of the first 200 participants (66% female, 35% male), with neuroendocrine neoplasms (NEN), adrenocortical cancer (ACC), SDH-deficient gastrointestinal stromal tumor (sdGIST), chordoma, medullary thyroid cancer (MTC), and other less commonly enrolled tumors totaling 35 different tumor types. Participants come from 46 US states and 9 countries. Early results show tumor-specific differences in mutations, treatment/management, PROs, and self-reported non-tumor health issues. The most common pathogenic germline mutations are SDHA/SDHB/SDHC in sdGIST and RET in MTC and other tumors. The most common pathogenic tumor mutations are TP53 and CTNNB1 in ACC, SDHA/B and TP53 in sdGIST, MEN1 in NEN, RET and HRAS in MTC, and SMARCB1 in chordoma. Clinically significant levels of anxiety and pain are more frequent in ACC, NEN, and sdGIST. Conclusions: By developing methods to provide value to rare tumor patients, using a large catchment area and opportunity for remote participation, and collecting data in a tumor-agnostic way, we can learn about multiple rare tumors and share findings more quickly than if each rare tumor was studied alone. We describe the MyPART cohort and challenges to overcome for successful longitudinal rare tumor natural history studies. Citation Format: Shadin Ahmed, Margarita Raygada, Robin Lockridge, Mary Frances Wedekind Malone, Jaydira Del Rivero, John W. Glod, Barbara J. Thomas, Donna Bernstein, Markku M. Miettinen, Liqiang Xi, Jung Kim, Manoj Tygagi, Mark Raffeld, Kenneth Aldape, Ashkan A. Malayeri, Abby B. Sandler, Brigitte C. Widemann, Karlyne M. Reilly. My Pediatric and Adult Rare Tumor Network (MyPART): integrating longitudinal, clinical, molecular, and patient-reported outcomes for rare tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4512.