BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: , missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).
| Authors | , ; Dorling, Leila; Carvalho, Sara; Allen, Jamie; González-Neira, Anna; Luccarini, Craig; Wahlström, Cecilia; Pooley, Karen A; Parsons, Michael T; Fortuno, Cristina; Wang, Qin; Bolla, Manjeet K; Dennis, Joe; Keeman, Renske; Alonso, M Rosario; Álvarez, Nuria; Herraez, Belen; Fernandez, Victoria; Núñez-Torres, Rocio; Osorio, Ana; Valcich, Jeanette; Li, Minerva; Törngren, Therese; Harrington, Patricia A; Baynes, Caroline; Conroy, Don M; Decker, Brennan; Fachal, Laura; Mavaddat, Nasim; Ahearn, Thomas; Aittomäki, Kristiina; Antonenkova, Natalia N; Arnold, Norbert; Arveux, Patrick; Ausems, Margreet G E M; Auvinen, Päivi; Becher, Heiko; Beckmann, Matthias W; Behrens, Sabine; Bermisheva, Marina; Bialkowska, Katarzyna; Blomqvist, Carl; Bogdanova, Natalia V; Bogdanova-Markov, Nadja; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Bremer, Michael; Briceno, Ignacio; Brüning, Thomas; Burwinkel, Barbara; Cameron, David A; Camp, Nicola J; Campbell, Archie; Carracedo, Angel; Castelao, Jose E; Cessna, Melissa H; Chanock, Stephen J; Christiansen, Hans; Collée, J Margriet; Cordina-Duverger, Emilie; Cornelissen, Sten; Czene, Kamila; Dörk, Thilo; Ekici, Arif B; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; Försti, Asta; Gabrielson, Marike; Gago-Dominguez, Manuela; Georgoulias, Vassilios; Gil, Fabian; Giles, Graham G; Glendon, Gord; Garcia, Encarna B Gómez; Alnæs, Grethe I Grenaker; Guénel, Pascal; Hadjisavvas, Andreas; Haeberle, Lothar; Hahnen, Eric; Hall, Per; Hamann, Ute; Harkness, Elaine F; Hartikainen, Jaana M; Hartman, Mikael; He, Wei; Heemskerk-Gerritsen, Bernadette A M; Hillemanns, Peter; Hogervorst, Frans B L; Hollestelle, Antoinette; Ho, Weang Kee; Hooning, Maartje J; Howell, Anthony; Humphreys, Keith; Idris, Faiza; Jakubowska, Anna; Jung, Audrey; Kapoor, Pooja Middha; Kerin, Michael J; Khusnutdinova, Elza; Kim, Sung-Won; Ko, Yon-Dschun; Kosma, Veli-Matti; Kristensen, Vessela N; Kyriacou, Kyriacos; Lakeman, Inge M M; Lee, Jong Won; Lee, Min Hyuk; Li, Jingmei; Lindblom, Annika; Lo, Wing-Yee; Loizidou, Maria A; Lophatananon, Artitaya; Lubinski, Jan; MacInnis, Robert J; Madsen, Michael J; Mannermaa, Arto; Manoochehri, Mehdi; Manoukian, Siranoush; Margolin, Sara; Martinez, Maria Elena; Maurer, Tabea; Mavroudis, Dimitrios; McLean, Catriona; Meindl, Alfons; Mensenkamp, Arjen R; Michailidou, Kyriaki; Miller, Nicola; Mohd Taib, Nur Aishah; Muir, Kenneth; Mulligan, Anna Marie; Nevanlinna, Heli; Newman, William G; Nordestgaard, Børge G; Ng, Pei-Sze; Oosterwijk, Jan C; Park, Sue K; Park-Simon, Tjoung-Won; Perez, Jose I A; Peterlongo, Paolo; Porteous, David J; Prajzendanc, Karolina; Prokofyeva, Darya; Radice, Paolo; Rashid, Muhammad U; Rhenius, Valerie; Rookus, Matti A; Rüdiger, Thomas; Saloustros, Emmanouil; Sawyer, Elinor J; Schmutzler, Rita K; Schneeweiss, Andreas; Schürmann, Peter; Shah, Mitul; Sohn, Christof; Southey, Melissa C; Surowy, Harald; Suvanto, Maija; Thanasitthichai, Somchai; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tzardi, Maria; Valova, Yana; van Asperen, Christi J; Van Dam, Rob M; van den Ouweland, Ans M W; van der Kolk, Lizet E; van Veen, Elke M; Wendt, Camilla; Williams, Justin A; Yang, Xiaohong R; Yoon, Sook-Yee; Zamora, M Pilar; Evans, D Gareth; de la Hoya, Miguel; Simard, Jacques; Antoniou, Antonis C; Borg, Åke; Andrulis, Irene L; Chang-Claude, Jenny; García-Closas, Montserrat; Chenevix-Trench, Georgia; Milne, Roger L; Pharoah, Paul D P; Schmidt, Marjanka K; Spurdle, Amanda B; Vreeswijk, Maaike P G; Benitez, Javier; Dunning, Alison M; Kvist, Anders; Teo, Soo H; Devilee, Peter; Easton, Douglas F |
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| Journal | The New England journal of medicine |
| Pages | 428-439 |
| Volume | 384 |
| Date | 1/01/2021 |
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| Funding Body | |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1056/NEJMoa1913948 |