The impact of coding germline variants on contralateral breast cancer risk and survival

Anna Morra, Nasim Mavaddat, Taru A. Muranen, Thomas U. Ahearn, Jamie Allen, Irene L. Andrulis, Päivi Auvinen, Heiko Becher, Sabine Behrens, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Nicola J. Camp, Sara Carvalho, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Georgia Chenevix-Trench, Kamila CzeneBrennan Decker, Joe Dennis, Thilo Dörk, Leila Dorling, Alison M. Dunning, Arif B. Ekici, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Willemina R.R. Geurts-Giele, Graham G. Giles, Pascal Guénel, Melanie Gündert, Eric Hahnen, Per Hall, Ute Hamann, Patricia A. Harrington, Wei He, Päivi Heikkilä, Maartje J. Hooning, Reiner Hoppe, Anthony Howell, Keith Humphreys, Anna Jakubowska, Audrey Y. Jung, Renske Keeman, Vessela N. Kristensen, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger Milne, Anna Marie Mulligan, William G. Newman, Tjoung Won Park-Simon, Paolo Peterlongo, Paul D.P. Pharoah, Valerie Rhenius, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Amanda B. Spurdle, Ian Tomlinson, Thérèse Truong, Elke M. van Veen, Maaike P.G. Vreeswijk, Qin Wang, Camilla Wendt, Xiaohong R. Yang, Heli Nevanlinna, Peter Devilee, Douglas F. Easton, Marjanka K. Schmidt, NBCS Collaborators, kConFab Investigators

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2 Citations (Scopus)


Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70–4.87), 2.31 (1.39–3.85), 8.29 (2.53–27.21), 2.25 (1.55–3.27), and 2.67 (1.33–5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13–2.07), 2.08 (0.95–4.57), and 1.39 (1.13–1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

Original languageEnglish
Pages (from-to)475-486
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - 2 Mar 2023


  • breast cancer susceptibility genes
  • coding germline variants
  • contralateral breast cancer risk
  • survival

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