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Background: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers., Patients and Methods: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies., Results: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation., Conclusions: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research., Competing Interests: Disclosure AJ: Honoraria: AstraZeneca. CH: Honoraria: Roche, Novartis; research funding: Boehringer Ingelheim; consulting or advisory board: Boehringer Ingelheim. CVG: Employed by Illumina since August 2021. LM reports non-financial support from Celgene outside the submitted work (travel expenses). MAu: Consulting or advisory board membership: Bristol-Myers Squibb, Ipsen, Merck KGaA, MSD Sharp & Dohme, Novartis, Pfizer, Roche, PharmaMar; research funding: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Exelixis, Ipsen, Merck KGaA, Novartis, Pfizer, PharmaMar, Roche; honoraria: Blueprint Medicines, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Merck KGaA, Pfizer, PharmaMar. PHoh: Advisory board membership: Roche, Deciphera, PharmaMar, Pfizer, BluMedicine, GSK; honoraria: Bristol-Meyers-Squibb, Astrazeneca; research funding: Novartis, Siemens. MK: Honoraria: Bayer, MSD, Eisai, Ipsen, Eli Lilly; research funding: Eli Lilly, Ipsen, Loxo Oncology. RFS: Consulting or advisory board membership: Astellas, Bristol-Myers Squibb, Celgene, Pfizer; research funding: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, PharmaMar, Roche; honoraria: Daiichi Sankyo, Pfizer. GF: Honoraria: Amgen, Armo Biosciences, Bayer, Bristol-Myers Squibb, Eli Lilly, HRA Pharma, Merck KGaA, MSD Sharp & Dohme, Pierre Fabre, Roche, Sanofi, Servier, Shire; research funding: Merck KGaA. SB: Consulting or advisory board membership: ADC Therapeutics, Blueprint Medicines, Daichii-Sankyo, Deciphera, Eli Lilly, Exelixis, Janssen-Cilag, Mundipharma, Novartis, Plexxikon; honoraria: Bayer, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, PharmaMar; research funding: Blueprint Medicines, Incyte, Novartis. JTS: Consulting or advisory board membership: AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Immunocore, Novartis, Roche, Shire; honoraria: AstraZeneca, Aurikamed, Baxalta, Bristol Myers Squibb, Celgene, Falk Foundation, iomedico, Immunocore, Novartis, Roche, Shire; research funding: Bristol-Myers Squibb, Celgene, Roche; minor equity in iTheranostics and Pharma15; member of the Board of Directors for Pharma15, all outside the submitted work. ALI: Honoraria: Bristol-Myers Squibb, Janssen-Cilag, Takeda, Roche. NvB: Consulting or advisory board membership: Novartis; honoraria: Novartis, Takeda. PJJ: Consulting or advisory board membership, honoraria, research funding, travel or accommodation expenses: Abbvie, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Novartis, Pfizer, Roche, Servier. KHM: Consulting: Celgene/BMS, Novartis, Jazz Pharmaceuticals, Pfizer; honoraria: Celgene/BMS, Daiichi Sankyo, Astellas, AbbVie, Novartis; research funding: Celgene. AS: Consulting or advisory board membership, honoraria: AGCT, AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Eli Lilly, Illumina, Janssen, MSD Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Thermo Fisher; research funding: Bayer, Bristol-Myers Squibb, Chugai. WW: Consulting or advisory board membership, honoraria: Agilent, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Illumina, Merck, MSD Sharp & Dohme, Pfizer, NewOncology, Novartis, Roche, Takeda; research funding: AstraZeneca, Bristol-Myers Squibb, MSD Sharp & Dohme, Roche. SF: Consulting or advisory board membership: Bayer, Illumina, Roche; honoraria: Amgen, Eli Lilly, PharmaMar, Roche; research funding: AstraZeneca, Pfizer, PharmaMar, Roche; travel or accommodation expenses: Amgen, Eli Lilly, Illumina, PharmaMar, Roche. ES: Honoraria: AstraZeneca, Illumina. All other authors have declared no conflicts of interest. Data sharing All evaluated germline variants can be found in Supplementary Table S5, available at https://doi.org/10.1016/j.annonc.2022.07.008. Sequencing data have been deposited in the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/datasets) under accession EGAS00001005537., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)