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Purpose: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome., Patients and Methods: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed., Results: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2 ) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC., Conclusion: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies., Competing Interests: Peter A. FaschingHonoraria: Roche, Novartis, Pfizer, ClinSol GmbH, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hexal, Lilly, Cepheid, BionTech, Pierre FabreConsulting or Advisory Role: Amgen, Teva, Celgene, Novartis, Pfizer, Roche, Puma Biotechnology, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hexal, Myelo Therapeutics GmbH, MacrogenicsResearch Funding: Novartis, BioNTech AG, Cepheid Eric C. PolleyResearch Funding: GRAIL Hans TeschHonoraria: Novartis, Roche Pharma AG, Pfizer, Amgen GmbH, AstraZeneca, Vifor Pharma, Lilly, Eisai, MSD Oncology, Grünethal, Bristol Myers Squibb, Mundipharma, ClinSol GmbHTravel, Accommodations, Expenses: Roche Pharma AG, Pfizer, Novartis, Amgen, AstraZeneca, Vifor Pharma, Lilly, Eisai Europe, MSD Oncology Johannes EttlHonoraria: Pfizer, Novartis, Lilly, Roche, Teva, AstraZeneca, Tesaro, Celgene, Pierre FabreConsulting or Advisory Role: Pfizer, Novartis, Lilly, Tesaro, Roche, Pierre Fabre, Daiichi SankyoSpeakers' Bureau: Pfizer, Roche, Lilly, Teva, Celgene, AstraZenecaResearch Funding: LillyTravel, Accommodations, Expenses: Pfizer, Teva, Celgene, Lilly, NovartisOther Relationship: Tesaro Friedrich OverkampHonoraria: Amgen, AstraZeneca, Bayer, Beiersdorf, Bristol Myers Squibb, Boehringer, Chugai, Celgene, Eisai, Gilead, Hexal, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Novonordisc, Riemser, Servier, ShireConsulting or Advisory Role: Amgen, Bristol Myers Squibb, Boehringer, Celgene, Clovis, Eusapharma, Hexal, Oncopeptides, Pfizer, Takeda Michael P. LuxHonoraria: Novartis, Pfizer, Lilly, AstraZeneca, Hexal, Eisai, Roche Pharma AG, Genomic Health, MSD OncologyConsulting or Advisory Role: Roche Pharma AG, Lilly, Pfizer, Novartis, AstraZeneca, Grünenthal Group, Genomic Health, Eisai, MSD Oncology, Pierre FabreSpeakers' Bureau: Roche Pharma AG, Novartis, Pfizer, Lilly, AstraZeneca, MSD Oncology, Eisai Germany, Exact SciencesResearch Funding: Discovering Hands, MSD Oncology, German Breast Group, Roche, PRAEGNANT Network, Grünenthal Group, SamantreeTravel, Accommodations, Expenses: Pfizer, Roche Pharma AGOther Relationship: MedacUncompensated Relationships: Pfizer, AstraZeneca Diana LüftnerHonoraria: AstraZeneca, Amgen, GlaxoSmithKline, Lilly, Pfizer, Novartis, L'Oreal, Teva Innovation Canada, SanofiResearch Funding: NovartisTravel, Accommodations, Expenses: Sanofi, Pfizer, Novartis Markus WallwienerHonoraria: Novartis, Pfizer, Roche, AstraZeneca, CelgeneConsulting or Advisory Role: Novartis, Roche, Pfizer, AstraZenecaResearch Funding: Novartis, Pfizer, AstraZeneca Volkmar MüllerHonoraria: AstraZeneca, Amgen, Daiichi Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, Tesaro, MSD Oncology, Pierre Fabre, Nektar, Genomic Health, Lilly, Seattle GeneticsConsulting or Advisory Role: Hexal, Roche, Amgen, Daiichi Sankyo, Nektar, Eisai, Lilly, Seattle GeneticsResearch Funding: Novartis, Seattle Genetics, Roche/GenentechTravel, Accommodations, Expenses: Roche, Pfizer, Daiichi Sankyo Erik BellevilleConsulting or Advisory Role: Novartis, HexalResearch Funding: Novartis, Hexal, Merrimack, AstraZeneca, PfizerTravel, Accommodations, Expenses: Onkowissen Michael UntchHonoraria: AstraZeneca, Art tempi, Bristol Myers Squibb, Celgene, Daiji Sankyo, Roche Pharma AG, Pfizer, Mundipharma, MSD Oncology, Pierre Fabre, Sanofi, Seattle Genetics, AgendiaConsulting or Advisory Role: Amgen, Abbvie, Celgene, Lilly, Mundipharma, Novartis, MSD Oncology, Pfizer, Roche Pharma AG, Agendia, Pierre Fabre, Seattle Genetics Hans-Christian KolbergStock and Other Ownership Interests: Theraclion, Phaon ScientificHonoraria: AstraZeneca, Amgen, Theraclion, Carl Zeiss Meditec, Novartis, Pfizer, Roche, Genomic Health, SurgVision, Theramex, MSD Oncology, OnkowissenConsulting or Advisory Role: SurgVision, AmgenTravel, Accommodations, Expenses: Carl Zeiss Meditec, Novartis, Pfizer, Amgen, Roche, LIV Pharma, Tesaro, Daiichi Sankyo, Genomic Health Arndt HartmannHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Boehringer Ingelheim, Abbvie, Janssen-Cilag, IpsenConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Cepheid, Qiagen, Janssen-Cilag, AstraZeneca, Ipsen, NanoString Technologies, Illumina, 3DHISTECH, DiaceuticsResearch Funding: Cepheid, BioNTech AG, Roche, Janssen-Cilag, NanoString Technologies, AstraZenecaExpert Testimony: NanoString Technologies Wolfgang JanniHonoraria: Novartis, Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo Europe GmbH, MSD OncologyConsulting or Advisory Role: Menarini Silicon Biosystems, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seattle GeneticsResearch Funding: Janssen Diagnostics, Menarini Silicon Biosystems, Novartis, Roche, Pfizer, Lilly, Amgen Pauline WimbergerHonoraria: AstraZeneca, MSD Oncology, Teva, Eisai, Novartis/Pfizer, Roche Pharma AG, Amgen, PfizerConsulting or Advisory Role: Amgen, AstraZeneca, MSD Oncology, Novartis, Roche Pharma AG, Tesaro, PharmaMarTravel, Accommodations, Expenses: Roche Pharma AG Florin-Andrei TaranHonoraria: Tesaro, NovartisConsulting or Advisory Role: GlaxoSmithKline, Roche, NovartisTravel, Accommodations, Expenses: GlaxoSmithKline Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Amgen, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche Diethelm WallwienerConsulting or Advisory Role: ConsalResearch Funding: Roche Pharma AG, Pfizer, Novartis Pharmaceuticals UK Ltd, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo/Lilly, Sanofi, GlaxoSmithKline, Merck Sharp & Dohme Sara Y. BruckerConsulting or Advisory Role: Roche, Novartis, Pfizer, Teva, Merck Sharp & Dohme, OlympusResearch Funding: Novartis, Roche, Pfizer, Genomic HealthTravel, Accommodations, Expenses: Novartis, Roche, Pfizer, Olympus, Teva, Merck Sharp & Dohme Andreas SchneeweissHonoraria: Roche Pharma AG, Celgene, AstraZeneca, Pfizer, Novartis, MSD Oncology, Lilly, TesaroResearch Funding: Roche Pharma AG, Celgene, Abbvie, Molecular PartnersExpert Testimony: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, Celgene Andreas D. HartkopfHonoraria: Roche, Novartis, Lilly, AstraZeneca, Merck Sharp & Dohme, Seagen, Daiichi Sankyo, GlaxoSmithKline, Genomic Health, Agendia, Pfizer, Amgen Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.