RT Journal Article SR Electronic T1 PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 800 OP 811 DO 10.1136/jmedgenet-2016-103839 VO 53 IS 12 A1 Melissa C Southey A1 David E Goldgar A1 Robert Winqvist A1 Katri Pylkäs A1 Fergus Couch A1 Marc Tischkowitz A1 William D Foulkes A1 Joe Dennis A1 Kyriaki Michailidou A1 Elizabeth J van Rensburg A1 Tuomas Heikkinen A1 Heli Nevanlinna A1 John L Hopper A1 Thilo Dörk A1 Kathleen BM Claes A1 Jorge Reis-Filho A1 Zhi Ling Teo A1 Paolo Radice A1 Irene Catucci A1 Paolo Peterlongo A1 Helen Tsimiklis A1 Fabrice A Odefrey A1 James G Dowty A1 Marjanka K Schmidt A1 Annegien Broeks A1 Frans B Hogervorst A1 Senno Verhoef A1 Jane Carpenter A1 Christine Clarke A1 Rodney J Scott A1 Peter A Fasching A1 Lothar Haeberle A1 Arif B Ekici A1 Matthias W Beckmann A1 Julian Peto A1 Isabel dos-Santos-Silva A1 Olivia Fletcher A1 Nichola Johnson A1 Manjeet K Bolla A1 Elinor J Sawyer A1 Ian Tomlinson A1 Michael J Kerin A1 Nicola Miller A1 Federik Marme A1 Barbara Burwinkel A1 Rongxi Yang A1 Pascal Guénel A1 Thérèse Truong A1 Florence Menegaux A1 Marie Sanchez A1 Stig Bojesen A1 Sune F Nielsen A1 Henrik Flyger A1 Javier Benitez A1 M Pilar Zamora A1 Jose Ignacio Arias Perez A1 Primitiva Menéndez A1 Hoda Anton-Culver A1 Susan Neuhausen A1 Argyrios Ziogas A1 Christina A Clarke A1 Hermann Brenner A1 Volker Arndt A1 Christa Stegmaier A1 Hiltrud Brauch A1 Thomas Brüning A1 Yon-Dschun Ko A1 Taru A Muranen A1 Kristiina Aittomäki A1 Carl Blomqvist A1 Natalia V Bogdanova A1 Natalia N Antonenkova A1 Annika Lindblom A1 Sara Margolin A1 Arto Mannermaa A1 Vesa Kataja A1 Veli-Matti Kosma A1 Jaana M Hartikainen A1 Amanda B Spurdle A1 kConFab Investigators A1 Australian Ovarian Cancer Study Group A1 Els Wauters A1 Dominiek Smeets A1 Benoit Beuselinck A1 Giuseppe Floris A1 Jenny Chang-Claude A1 Anja Rudolph A1 Petra Seibold A1 Dieter Flesch-Janys A1 Janet E Olson A1 Celine Vachon A1 Vernon S Pankratz A1 Catriona McLean A1 Christopher A Haiman A1 Brian E Henderson A1 Fredrick Schumacher A1 Loic Le Marchand A1 Vessela Kristensen A1 Grethe Grenaker Alnæs A1 Wei Zheng A1 David J Hunter A1 Sara Lindstrom A1 Susan E Hankinson A1 Peter Kraft A1 Irene Andrulis A1 Julia A Knight A1 Gord Glendon A1 Anna Marie Mulligan A1 Arja Jukkola-Vuorinen A1 Mervi Grip A1 Saila Kauppila A1 Peter Devilee A1 Robert A E M Tollenaar A1 Caroline Seynaeve A1 Antoinette Hollestelle A1 Montserrat Garcia-Closas A1 Jonine Figueroa A1 Stephen J Chanock A1 Jolanta Lissowska A1 Kamila Czene A1 Hatef Darabi A1 Mikael Eriksson A1 Diana M Eccles A1 Sajjad Rafiq A1 William J Tapper A1 Sue M Gerty A1 Maartje J Hooning A1 John W M Martens A1 J Margriet Collée A1 Madeleine Tilanus-Linthorst A1 Per Hall A1 Jingmei Li A1 Judith S Brand A1 Keith Humphreys A1 Angela Cox A1 Malcolm W R Reed A1 Craig Luccarini A1 Caroline Baynes A1 Alison M Dunning A1 Ute Hamann A1 Diana Torres A1 Hans Ulrich Ulmer A1 Thomas Rüdiger A1 Anna Jakubowska A1 Jan Lubinski A1 Katarzyna Jaworska A1 Katarzyna Durda A1 Susan Slager A1 Amanda E Toland A1 Christine B Ambrosone A1 Drakoulis Yannoukakos A1 Anthony Swerdlow A1 Alan Ashworth A1 Nick Orr A1 Michael Jones A1 Anna González-Neira A1 Guillermo Pita A1 M Rosario Alonso A1 Nuria Álvarez A1 Daniel Herrero A1 Daniel C Tessier A1 Daniel Vincent A1 Francois Bacot A1 Jacques Simard A1 Martine Dumont A1 Penny Soucy A1 Rosalind Eeles A1 Kenneth Muir A1 Fredrik Wiklund A1 Henrik Gronberg A1 Johanna Schleutker A1 Børge G Nordestgaard A1 Maren Weischer A1 Ruth C Travis A1 David Neal A1 Jenny L Donovan A1 Freddie C Hamdy A1 Kay-Tee Khaw A1 Janet L Stanford A1 William J Blot A1 Stephen Thibodeau A1 Daniel J Schaid A1 Joseph L Kelley A1 Christiane Maier A1 Adam S Kibel A1 Cezary Cybulski A1 Lisa Cannon-Albright A1 Katja Butterbach A1 Jong Park A1 Radka Kaneva A1 Jyotsna Batra A1 Manuel R Teixeira A1 Zsofia Kote-Jarai A1 Ali Amin Al Olama A1 Sara Benlloch A1 Stefan P Renner A1 Arndt Hartmann A1 Alexander Hein A1 Matthias Ruebner A1 Diether Lambrechts A1 Els Van Nieuwenhuysen A1 Ignace Vergote A1 Sandrina Lambretchs A1 Jennifer A Doherty A1 Mary Anne Rossing A1 Stefan Nickels A1 Ursula Eilber A1 Shan Wang-Gohrke A1 Kunle Odunsi A1 Lara E Sucheston-Campbell A1 Grace Friel A1 Galina Lurie A1 Jeffrey L Killeen A1 Lynne R Wilkens A1 Marc T Goodman A1 Ingo Runnebaum A1 Peter A Hillemanns A1 Liisa M Pelttari A1 Ralf Butzow A1 Francesmary Modugno A1 Robert P Edwards A1 Roberta B Ness A1 Kirsten B Moysich A1 Andreas du Bois A1 Florian Heitz A1 Philipp Harter A1 Stefan Kommoss A1 Beth Y Karlan A1 Christine Walsh A1 Jenny Lester A1 Allan Jensen A1 Susanne Krüger Kjaer A1 Estrid Høgdall A1 Bernard Peissel A1 Bernardo Bonanni A1 Loris Bernard A1 Ellen L Goode A1 Brooke L Fridley A1 Robert A Vierkant A1 Julie M Cunningham A1 Melissa C Larson A1 Zachary C Fogarty A1 Kimberly R Kalli A1 Dong Liang A1 Karen H Lu A1 Michelle A T Hildebrandt A1 Xifeng Wu A1 Douglas A Levine A1 Fanny Dao A1 Maria Bisogna A1 Andrew Berchuck A1 Edwin S Iversen A1 Jeffrey R Marks A1 Lucy Akushevich A1 Daniel W Cramer A1 Joellen Schildkraut A1 Kathryn L Terry A1 Elizabeth M Poole A1 Meir Stampfer A1 Shelley S Tworoger A1 Elisa V Bandera A1 Irene Orlow A1 Sara H Olson A1 Line Bjorge A1 Helga B Salvesen A1 Anne M van Altena A1 Katja K H Aben A1 Lambertus A Kiemeney A1 Leon F A G Massuger A1 Tanja Pejovic A1 Yukie Bean A1 Angela Brooks-Wilson A1 Linda E Kelemen A1 Linda S Cook A1 Nhu D Le A1 Bohdan Górski A1 Jacek Gronwald A1 Janusz Menkiszak A1 Claus K Høgdall A1 Lene Lundvall A1 Lotte Nedergaard A1 Svend Aage Engelholm A1 Ed Dicks A1 Jonathan Tyrer A1 Ian Campbell A1 Iain McNeish A1 James Paul A1 Nadeem Siddiqui A1 Rosalind Glasspool A1 Alice S Whittemore A1 Joseph H Rothstein A1 Valerie McGuire A1 Weiva Sieh A1 Hui Cai A1 Xiao-Ou Shu A1 Rachel T Teten A1 Rebecca Sutphen A1 John R McLaughlin A1 Steven A Narod A1 Catherine M Phelan A1 Alvaro N Monteiro A1 David Fenstermacher A1 Hui-Yi Lin A1 Jennifer B Permuth A1 Thomas A Sellers A1 Y Ann Chen A1 Ya-Yu Tsai A1 Zhihua Chen A1 Aleksandra Gentry-Maharaj A1 Simon A Gayther A1 Susan J Ramus A1 Usha Menon A1 Anna H Wu A1 Celeste L Pearce A1 David Van Den Berg A1 Malcolm C Pike A1 Agnieszka Dansonka-Mieszkowska A1 Joanna Plisiecka-Halasa A1 Joanna Moes-Sosnowska A1 Jolanta Kupryjanczyk A1 Paul DP Pharoah A1 Honglin Song A1 Ingrid Winship A1 Georgia Chenevix-Trench A1 Graham G Giles A1 Sean V Tavtigian A1 Doug F Easton A1 Roger L Milne YR 2016 UL http://jmg.bmj.com/content/53/12/800.abstract AB Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.