R Institute, Division of Dermatology, University of Utah, Salt Lake City (Feng, Goldgar); Division of Clinical Diagnostics, Ambry Genetics Inc, Aliso Viejo, California (McFarland, Pesaran, Huether, LaDuca, Chao, Dolinsky); Now, Division of Genetics and Genomics, Department of Pediatrics, University of California-Irvine (Chao)AbstractImportance–Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime threat of breast cancer. Nevertheless, the relevance of germline variants in other genes from multigene hereditary cancer testing panels just isn’t well defined. Objective–To ascertain the dangers of breast cancer related with germline variants in cancer predisposition genes. Design and style, Setting, and Participants–A study population of 65 057 sufferers with breast cancer getting germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations in between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer danger have been estimated in a case-control evaluation of patients with breast cancer and Exome Aggregation Consortium reference controls. The females underwent testing involving March 15, 2012, and June 30, 2016.Corresponding Author: Fergus J. Couch, PhD, Division of Laboratory Medicine and Pathology, Mayo Clinic, Stabile 2-42, 200 Initial St SW, Rochester, MN 55905 ([email protected]). Meeting Presentation: A portion of this study was presented at the 2016 San Antonio Breast Cancer Symposium; December 9, 2016; San Antonio, Texas. Author Contributions: Drs Couch, Shimelis, and Hu contributed equally towards the study. Dr Couch and Ms Dolinsky had full access to all of the information in the study and take responsibility for the integrity with the data and also the accuracy with the information evaluation. Study notion and style: Couch, Goldgar, Dolinsky. Acquisition, evaluation, or interpretation of information: All authors., Drafting of your manuscript: Couch, Shimelis, Hu, LaDuca, Goldgar, Dolinsky.TWEAK/TNFSF12 Protein Gene ID , Critical revision of the manuscript for critical intellectual content material: Couch, Shimelis, Hu, Polley, Na, Hallberg, Thomas, Lilyquist, Feng, McFarland, Pesaran, Huether, LaDuca, Chao, Goldgar, Dolinsky.IFN-beta Protein MedChemExpress , Statistical evaluation: Shimelis, Hart, Polley, Na, Lilyquist, Feng, Goldgar.PMID:35567400 , Obtained funding: Couch., Administrative, technical, or material support: Couch, Hallberg, Moore, Thomas, McFarland, Huether, Dolinsky., Supervision: Couch, Hart, Chao, Goldgar, Dolinsky. Conflict of Interest Disclosures: Dr Huether and Mss McFarland, Pesaran, LaDuca, and Dolinsky are workers of Ambry Genetics Inc. Dr Chao was employed by Ambry Genetics Inc at the time with the study. No other conflicts have been reported.Couch et al.PageMain Outcomes and Measures–Breast cancer threat conferred by pathogenic variants in nonBRCA1 and non-BRCA2 predisposition genes. Results–The mean (SD) age at diagnosis for the 65 057 ladies incorporated in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.two . Following exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes had been associated with higher or moderately improved dangers ofbreast cancer: ATM (OR, two.78; 95 CI, 2.22-3.62), BARD1 (OR, two.16; 95 CI, 1.31-3.63), CHEK2 (OR, 1.48; 95 CI, 1.31-1.67), PALB2 (OR, 7.46; 95 CI, five.12-11.19), and RAD51D (OR, 3.07; 95 CI, 1.21-7.88). Conversely, v.