Standard
Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset. / Davidson, Aimee L.; Michailidou, Kyriaki; Parsons, Michael T.; Fortuno, Cristina; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Naven, Marc; Abubakar, Mustapha; Ahearn, Thomas U.; Alonso, M. Rosario; Andrulis, Irene L.; Antoniou, Antonis C.; Auvinen, Päivi; Behrens, Sabine; Bermisheva, Marina A.; Bogdanova, Natalia V.; Bojesen, Stig E.; Brüning, Thomas; Byers, Helen J.; Camp, Nicola J.; Campbell, Archie; Castelao, Jose E.; Cessna, Melissa H.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Sahlberg, Kristine K.; Børresen-Dale, Anne-Lise; Gram, Inger Torhild; Olsen, Karina Standahl; Engebråten, Olav; Naume, Bjørn; Geisler, Jürgen; OSBREAC; Grenaker Alnæs, Grethe I.; Collée, J. Margriet; Czene, Kamila; Dörk, Thilo; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine D.; Flyger, Henrik; Gago-Dominguez, Manuela; García-Closas, Montserrat; Glendon, Gord; González-Neira, Anna; Grassmann, Felix; Gronwald, Jacek; Guénel, Pascal; Hadjisavvas, Andreas; Haeberle, Lothar; Hall, Per; Hamann, Ute; Hartman, Mikael; Ho, Peh Joo; Hooning, Maartje J.; Hoppe, Reiner; Howell, Anthony; Amor, David; Andrews, Lesley; Antill, Yoland; Balleine, Rosemary; Beesley, Jonathan; Bennett, Ian; Bogwitz, Michael; Bodek, Simon; Botes, Leon; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burke, Jo; Butow, Phyllis; Caldon, Liz; Campbell, Ian; Cao, Michelle; Chakrabarti, Anannya; Chauhan, Deepa; Chauhan, Manisha; Christian, Alice; Cohen, Paul; Colley, Alison; Crook, Ashley; Cui, James; Courtney, Eliza; Cummings, Margaret; Dawson, Sarah-Jane; deFazio, Anna; Delatycki, Martin; Dickson, Rebecca; Dixon, Joanne; Edwards, Stacey; Farshid, Gelareh; Fellows, Andrew; Fenton, Georgina; Field, Michael; Flanagan, James; Fong, Peter; Forrest, Laura; Fox, Stephen; French, Juliet; Friedlander, Michael; Gaff, Clara; Gattas, Mike; George, Peter; Greening, Sian; Harris, Marion; Hart, Stewart; Harraka, Philip; Hayward, Nick; Hopper, John; Hoskins, Cass; Hunt, Clare; Jenkins, Mark; Kidd, Alexa; Kirk, Judy; Koehler, Jessica; Kollias, James; Lakhani, Sunil; Lawrence, Mitchell; Lee, Jason; Li, Shuai; Lindeman, Geoff; Lippey, Jocelyn; Lipton, Lara; Lobb, Liz; Loi, Sherene; Mann, Graham; Marsh, Deborah; McLachlan, Sue Anne; Meiser, Bettina; Nightingale, Sophie; O'Connell, Shona; O'Sullivan, Sarah; Ortega, David Gallego; Pachter, Nick; Pang, Jia-Min; Pathak, Gargi; Patterson, Briony; Pearn, Amy; Phillips, Kelly; Pieper, Ellen; Ramus, Susan; Rickard, Edwina; Ragunathan, Abi; Robinson, Bridget; Saleh, Mona; Skandarajah, Anita; Salisbury, Elizabeth; Saunders, Christobel; Saunus, Jodi; Savas, Peter; Scott, Rodney; Scott, Clare; Sexton, Adrienne; Shaw, Joanne; Shelling, Andrew; Srinivasa, Shweta; Simpson, Peter; Taylor, Jessica; Taylor, Renea; Thorne, Heather; Trainer, Alison; Tucker, Kathy; Visvader, Jane; Walker, Logan; Williams, Rachael; Winship, Ingrid; Young, Mary Ann; Zaheed, Milita; Jakubowska, Anna; Khusnutdinova, Elza K.; Kristensen, Vessela N.; Li, Jingmei; Lim, Joanna; Lindblom, Annika; Liu, Jenny; Lophatananon, Artitaya; Mannermaa, Arto; Mavroudis, Dimitrios A.; Mensenkamp, Arjen R.; Milne, Roger L.; Muir, Kenneth R.; Newman, William G.; Obi, Nadia; Panayiotidis, Mihalis I.; Park, Sue K.; Park-Simon, Tjoung-Won; Peterlongo, Paolo; Radice, Paolo; Rashid, Muhammad U.; Rhenius, Valerie; Saloustros, Emmanouil; Sawyer, Elinor J.; Schmidt, Marjanka K.; Seibold, Petra; Shah, Mitul; Southey, Melissa C.; Teo, Soo Hwang; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; van de Beek, Irma; van der Hout, Annemieke H.; Wendt, Camilla C.; Dunning, Alison M.; Pharoah, Paul D.P.; Devilee, Peter; Easton, Douglas F.; James, Paul A.; Spurdle, Amanda B.
In:
American Journal of Human Genetics, Vol. 111, No. 9, 05.09.2024, p. 2059-2069.
Research output: Contribution to journal › Article › peer-review
Harvard
Davidson, AL, Michailidou, K, Parsons, MT, Fortuno, C, Bolla, MK, Wang, Q, Dennis, J, Naven, M, Abubakar, M, Ahearn, TU, Alonso, MR, Andrulis, IL, Antoniou, AC, Auvinen, P, Behrens, S
, Bermisheva, MA, Bogdanova, NV, Bojesen, SE, Brüning, T, Byers, HJ, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Sahlberg, KK, Børresen-Dale, A-L, Gram, IT, Olsen, KS, Engebråten, O, Naume, B, Geisler, J, OSBREAC, Grenaker Alnæs, GI, Collée, JM, Czene, K, Dörk, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gago-Dominguez, M, García-Closas, M, Glendon, G, González-Neira, A, Grassmann, F, Gronwald, J, Guénel, P, Hadjisavvas, A, Haeberle, L, Hall, P, Hamann, U, Hartman, M, Ho, PJ, Hooning, MJ, Hoppe, R, Howell, A, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Bennett, I, Bogwitz, M, Bodek, S, Botes, L, Brennan, M, Brown, M, Buckley, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Cao, M, Chakrabarti, A, Chauhan, D, Chauhan, M, Christian, A, Cohen, P, Colley, A, Crook, A, Cui, J, Courtney, E, Cummings, M, Dawson, S-J, deFazio, A, Delatycki, M, Dickson, R, Dixon, J, Edwards, S, Farshid, G, Fellows, A, Fenton, G, Field, M, Flanagan, J, Fong, P, Forrest, L, Fox, S, French, J, Friedlander, M, Gaff, C, Gattas, M, George, P, Greening, S, Harris, M, Hart, S, Harraka, P, Hayward, N, Hopper, J, Hoskins, C, Hunt, C, Jenkins, M, Kidd, A, Kirk, J, Koehler, J, Kollias, J, Lakhani, S, Lawrence, M, Lee, J, Li, S, Lindeman, G, Lippey, J, Lipton, L, Lobb, L, Loi, S, Mann, G, Marsh, D, McLachlan, SA, Meiser, B, Nightingale, S, O'Connell, S, O'Sullivan, S, Ortega, DG, Pachter, N, Pang, J-M, Pathak, G, Patterson, B, Pearn, A, Phillips, K, Pieper, E, Ramus, S, Rickard, E, Ragunathan, A, Robinson, B, Saleh, M, Skandarajah, A, Salisbury, E, Saunders, C, Saunus, J, Savas, P, Scott, R, Scott, C, Sexton, A, Shaw, J, Shelling, A, Srinivasa, S, Simpson, P, Taylor, J, Taylor, R, Thorne, H, Trainer, A, Tucker, K, Visvader, J, Walker, L, Williams, R, Winship, I, Young, MA, Zaheed, M, Jakubowska, A
, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, J, Lindblom, A, Liu, J, Lophatananon, A, Mannermaa, A, Mavroudis, DA, Mensenkamp, AR, Milne, RL, Muir, KR, Newman, WG, Obi, N, Panayiotidis, MI, Park, SK, Park-Simon, T-W, Peterlongo, P, Radice, P, Rashid, MU, Rhenius, V, Saloustros, E, Sawyer, EJ, Schmidt, MK, Seibold, P, Shah, M, Southey, MC, Teo, SH, Tomlinson, I, Torres, D, Truong, T, van de Beek, I, van der Hout, AH, Wendt, CC, Dunning, AM, Pharoah, PDP, Devilee, P, Easton, DF, James, PA & Spurdle, AB 2024, '
Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset',
American Journal of Human Genetics, vol. 111, no. 9, pp. 2059-2069.
https://doi.org/10.1016/j.ajhg.2024.07.004,
https://doi.org/10.1016/j.ajhg.2024.07.004APA
Davidson, A. L., Michailidou, K., Parsons, M. T., Fortuno, C., Bolla, M. K., Wang, Q., Dennis, J., Naven, M., Abubakar, M., Ahearn, T. U., Alonso, M. R., Andrulis, I. L., Antoniou, A. C., Auvinen, P., Behrens, S.
, Bermisheva, M. A., Bogdanova, N. V., Bojesen, S. E., Brüning, T., ... Spurdle, A. B. (2024).
Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.
American Journal of Human Genetics,
111(9), 2059-2069.
https://doi.org/10.1016/j.ajhg.2024.07.004,
https://doi.org/10.1016/j.ajhg.2024.07.004Vancouver
Author
Davidson, Aimee L. ; Michailidou, Kyriaki ; Parsons, Michael T. ; Fortuno, Cristina ; Bolla, Manjeet K. ; Wang, Qin ; Dennis, Joe ; Naven, Marc ; Abubakar, Mustapha ; Ahearn, Thomas U. ; Alonso, M. Rosario ; Andrulis, Irene L. ; Antoniou, Antonis C. ; Auvinen, Päivi ; Behrens, Sabine
; Bermisheva, Marina A. ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Brüning, Thomas ; Byers, Helen J. ; Camp, Nicola J. ; Campbell, Archie ; Castelao, Jose E. ; Cessna, Melissa H. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Chenevix-Trench, Georgia ; Sahlberg, Kristine K. ; Børresen-Dale, Anne-Lise ; Gram, Inger Torhild ; Olsen, Karina Standahl ; Engebråten, Olav ; Naume, Bjørn ; Geisler, Jürgen ; OSBREAC ; Grenaker Alnæs, Grethe I. ; Collée, J. Margriet ; Czene, Kamila ; Dörk, Thilo ; Eriksson, Mikael ; Evans, D. Gareth ; Fasching, Peter A. ; Figueroa, Jonine D. ; Flyger, Henrik ; Gago-Dominguez, Manuela ; García-Closas, Montserrat ; Glendon, Gord ; González-Neira, Anna ; Grassmann, Felix ; Gronwald, Jacek ; Guénel, Pascal ; Hadjisavvas, Andreas ; Haeberle, Lothar ; Hall, Per ; Hamann, Ute ; Hartman, Mikael ; Ho, Peh Joo ; Hooning, Maartje J. ; Hoppe, Reiner ; Howell, Anthony ; Amor, David ; Andrews, Lesley ; Antill, Yoland ; Balleine, Rosemary ; Beesley, Jonathan ; Bennett, Ian ; Bogwitz, Michael ; Bodek, Simon ; Botes, Leon ; Brennan, Meagan ; Brown, Melissa ; Buckley, Michael ; Burke, Jo ; Butow, Phyllis ; Caldon, Liz ; Campbell, Ian ; Cao, Michelle ; Chakrabarti, Anannya ; Chauhan, Deepa ; Chauhan, Manisha ; Christian, Alice ; Cohen, Paul ; Colley, Alison ; Crook, Ashley ; Cui, James ; Courtney, Eliza ; Cummings, Margaret ; Dawson, Sarah-Jane ; deFazio, Anna ; Delatycki, Martin ; Dickson, Rebecca ; Dixon, Joanne ; Edwards, Stacey ; Farshid, Gelareh ; Fellows, Andrew ; Fenton, Georgina ; Field, Michael ; Flanagan, James ; Fong, Peter ; Forrest, Laura ; Fox, Stephen ; French, Juliet ; Friedlander, Michael ; Gaff, Clara ; Gattas, Mike ; George, Peter ; Greening, Sian ; Harris, Marion ; Hart, Stewart ; Harraka, Philip ; Hayward, Nick ; Hopper, John ; Hoskins, Cass ; Hunt, Clare ; Jenkins, Mark ; Kidd, Alexa ; Kirk, Judy ; Koehler, Jessica ; Kollias, James ; Lakhani, Sunil ; Lawrence, Mitchell ; Lee, Jason ; Li, Shuai ; Lindeman, Geoff ; Lippey, Jocelyn ; Lipton, Lara ; Lobb, Liz ; Loi, Sherene ; Mann, Graham ; Marsh, Deborah ; McLachlan, Sue Anne ; Meiser, Bettina ; Nightingale, Sophie ; O'Connell, Shona ; O'Sullivan, Sarah ; Ortega, David Gallego ; Pachter, Nick ; Pang, Jia-Min ; Pathak, Gargi ; Patterson, Briony ; Pearn, Amy ; Phillips, Kelly ; Pieper, Ellen ; Ramus, Susan ; Rickard, Edwina ; Ragunathan, Abi ; Robinson, Bridget ; Saleh, Mona ; Skandarajah, Anita ; Salisbury, Elizabeth ; Saunders, Christobel ; Saunus, Jodi ; Savas, Peter ; Scott, Rodney ; Scott, Clare ; Sexton, Adrienne ; Shaw, Joanne ; Shelling, Andrew ; Srinivasa, Shweta ; Simpson, Peter ; Taylor, Jessica ; Taylor, Renea ; Thorne, Heather ; Trainer, Alison ; Tucker, Kathy ; Visvader, Jane ; Walker, Logan ; Williams, Rachael ; Winship, Ingrid ; Young, Mary Ann ; Zaheed, Milita ; Jakubowska, Anna
; Khusnutdinova, Elza K. ; Kristensen, Vessela N. ; Li, Jingmei ; Lim, Joanna ; Lindblom, Annika ; Liu, Jenny ; Lophatananon, Artitaya ; Mannermaa, Arto ; Mavroudis, Dimitrios A. ; Mensenkamp, Arjen R. ; Milne, Roger L. ; Muir, Kenneth R. ; Newman, William G. ; Obi, Nadia ; Panayiotidis, Mihalis I. ; Park, Sue K. ; Park-Simon, Tjoung-Won ; Peterlongo, Paolo ; Radice, Paolo ; Rashid, Muhammad U. ; Rhenius, Valerie ; Saloustros, Emmanouil ; Sawyer, Elinor J. ; Schmidt, Marjanka K. ; Seibold, Petra ; Shah, Mitul ; Southey, Melissa C. ; Teo, Soo Hwang ; Tomlinson, Ian ; Torres, Diana ; Truong, Thérèse ; van de Beek, Irma ; van der Hout, Annemieke H. ; Wendt, Camilla C. ; Dunning, Alison M. ; Pharoah, Paul D.P. ; Devilee, Peter ; Easton, Douglas F. ; James, Paul A. ; Spurdle, Amanda B. /
Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset. In:
American Journal of Human Genetics. 2024 ; Vol. 111, No. 9. pp. 2059-2069.
BibTeX
@article{19b2f2cbdc8e4dda899e730feb7dfb77,
title = "Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset",
abstract = "Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.",
keywords = "Adult, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Fanconi Anemia Complementation Group N Protein/genetics, Female, Genetic Predisposition to Disease, Germ-Line Mutation/genetics, Humans, Middle Aged, Mutation, Missense/genetics, Tumor Suppressor Protein p53/genetics, ACMG/AMP, variant classification, BP5, breast cancer, co-observation, genetics, sequencing data",
author = "Davidson, {Aimee L.} and Kyriaki Michailidou and Parsons, {Michael T.} and Cristina Fortuno and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Marc Naven and Mustapha Abubakar and Ahearn, {Thomas U.} and Alonso, {M. Rosario} and Andrulis, {Irene L.} and Antoniou, {Antonis C.} and P{\"a}ivi Auvinen and Sabine Behrens and Bermisheva, {Marina A.} and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Thomas Br{\"u}ning and Byers, {Helen J.} and Camp, {Nicola J.} and Archie Campbell and Castelao, {Jose E.} and Cessna, {Melissa H.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Georgia Chenevix-Trench and Sahlberg, {Kristine K.} and Anne-Lise B{\o}rresen-Dale and Gram, {Inger Torhild} and Olsen, {Karina Standahl} and Olav Engebr{\aa}ten and Bj{\o}rn Naume and J{\"u}rgen Geisler and OSBREAC and {Grenaker Aln{\ae}s}, {Grethe I.} and Coll{\'e}e, {J. Margriet} and Kamila Czene and Thilo D{\"o}rk and Mikael Eriksson and Evans, {D. Gareth} and Fasching, {Peter A.} and Figueroa, {Jonine D.} and Henrik Flyger and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Gord Glendon and Anna Gonz{\'a}lez-Neira and Felix Grassmann and Jacek Gronwald and Pascal Gu{\'e}nel and Andreas Hadjisavvas and Lothar Haeberle and Per Hall and Ute Hamann and Mikael Hartman and Ho, {Peh Joo} and Hooning, {Maartje J.} and Reiner Hoppe and Anthony Howell and David Amor and Lesley Andrews and Yoland Antill and Rosemary Balleine and Jonathan Beesley and Ian Bennett and Michael Bogwitz and Simon Bodek and Leon Botes and Meagan Brennan and Melissa Brown and Michael Buckley and Jo Burke and Phyllis Butow and Liz Caldon and Ian Campbell and Michelle Cao and Anannya Chakrabarti and Deepa Chauhan and Manisha Chauhan and Alice Christian and Paul Cohen and Alison Colley and Ashley Crook and James Cui and Eliza Courtney and Margaret Cummings and Sarah-Jane Dawson and Anna deFazio and Martin Delatycki and Rebecca Dickson and Joanne Dixon and Stacey Edwards and Gelareh Farshid and Andrew Fellows and Georgina Fenton and Michael Field and James Flanagan and Peter Fong and Laura Forrest and Stephen Fox and Juliet French and Michael Friedlander and Clara Gaff and Mike Gattas and Peter George and Sian Greening and Marion Harris and Stewart Hart and Philip Harraka and Nick Hayward and John Hopper and Cass Hoskins and Clare Hunt and Mark Jenkins and Alexa Kidd and Judy Kirk and Jessica Koehler and James Kollias and Sunil Lakhani and Mitchell Lawrence and Jason Lee and Shuai Li and Geoff Lindeman and Jocelyn Lippey and Lara Lipton and Liz Lobb and Sherene Loi and Graham Mann and Deborah Marsh and McLachlan, {Sue Anne} and Bettina Meiser and Sophie Nightingale and Shona O'Connell and Sarah O'Sullivan and Ortega, {David Gallego} and Nick Pachter and Jia-Min Pang and Gargi Pathak and Briony Patterson and Amy Pearn and Kelly Phillips and Ellen Pieper and Susan Ramus and Edwina Rickard and Abi Ragunathan and Bridget Robinson and Mona Saleh and Anita Skandarajah and Elizabeth Salisbury and Christobel Saunders and Jodi Saunus and Peter Savas and Rodney Scott and Clare Scott and Adrienne Sexton and Joanne Shaw and Andrew Shelling and Shweta Srinivasa and Peter Simpson and Jessica Taylor and Renea Taylor and Heather Thorne and Alison Trainer and Kathy Tucker and Jane Visvader and Logan Walker and Rachael Williams and Ingrid Winship and Young, {Mary Ann} and Milita Zaheed and Anna Jakubowska and Khusnutdinova, {Elza K.} and Kristensen, {Vessela N.} and Jingmei Li and Joanna Lim and Annika Lindblom and Jenny Liu and Artitaya Lophatananon and Arto Mannermaa and Mavroudis, {Dimitrios A.} and Mensenkamp, {Arjen R.} and Milne, {Roger L.} and Muir, {Kenneth R.} and Newman, {William G.} and Nadia Obi and Panayiotidis, {Mihalis I.} and Park, {Sue K.} and Tjoung-Won Park-Simon and Paolo Peterlongo and Paolo Radice and Rashid, {Muhammad U.} and Valerie Rhenius and Emmanouil Saloustros and Sawyer, {Elinor J.} and Schmidt, {Marjanka K.} and Petra Seibold and Mitul Shah and Southey, {Melissa C.} and Teo, {Soo Hwang} and Ian Tomlinson and Diana Torres and Th{\'e}r{\`e}se Truong and {van de Beek}, Irma and {van der Hout}, {Annemieke H.} and Wendt, {Camilla C.} and Dunning, {Alison M.} and Pharoah, {Paul D.P.} and Peter Devilee and Easton, {Douglas F.} and James, {Paul A.} and Spurdle, {Amanda B.}",
year = "2024",
month = sep,
day = "5",
doi = "10.1016/j.ajhg.2024.07.004",
language = "English",
volume = "111",
pages = "2059--2069",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "9",
}
RIS
TY - JOUR
T1 - Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset
AU - Davidson, Aimee L.
AU - Michailidou, Kyriaki
AU - Parsons, Michael T.
AU - Fortuno, Cristina
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Dennis, Joe
AU - Naven, Marc
AU - Abubakar, Mustapha
AU - Ahearn, Thomas U.
AU - Alonso, M. Rosario
AU - Andrulis, Irene L.
AU - Antoniou, Antonis C.
AU - Auvinen, Päivi
AU - Behrens, Sabine
AU - Bermisheva, Marina A.
AU - Bogdanova, Natalia V.
AU - Bojesen, Stig E.
AU - Brüning, Thomas
AU - Byers, Helen J.
AU - Camp, Nicola J.
AU - Campbell, Archie
AU - Castelao, Jose E.
AU - Cessna, Melissa H.
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Chenevix-Trench, Georgia
AU - Sahlberg, Kristine K.
AU - Børresen-Dale, Anne-Lise
AU - Gram, Inger Torhild
AU - Olsen, Karina Standahl
AU - Engebråten, Olav
AU - Naume, Bjørn
AU - Geisler, Jürgen
AU - OSBREAC, null
AU - Grenaker Alnæs, Grethe I.
AU - Collée, J. Margriet
AU - Czene, Kamila
AU - Dörk, Thilo
AU - Eriksson, Mikael
AU - Evans, D. Gareth
AU - Fasching, Peter A.
AU - Figueroa, Jonine D.
AU - Flyger, Henrik
AU - Gago-Dominguez, Manuela
AU - García-Closas, Montserrat
AU - Glendon, Gord
AU - González-Neira, Anna
AU - Grassmann, Felix
AU - Gronwald, Jacek
AU - Guénel, Pascal
AU - Hadjisavvas, Andreas
AU - Haeberle, Lothar
AU - Hall, Per
AU - Hamann, Ute
AU - Hartman, Mikael
AU - Ho, Peh Joo
AU - Hooning, Maartje J.
AU - Hoppe, Reiner
AU - Howell, Anthony
AU - Amor, David
AU - Andrews, Lesley
AU - Antill, Yoland
AU - Balleine, Rosemary
AU - Beesley, Jonathan
AU - Bennett, Ian
AU - Bogwitz, Michael
AU - Bodek, Simon
AU - Botes, Leon
AU - Brennan, Meagan
AU - Brown, Melissa
AU - Buckley, Michael
AU - Burke, Jo
AU - Butow, Phyllis
AU - Caldon, Liz
AU - Campbell, Ian
AU - Cao, Michelle
AU - Chakrabarti, Anannya
AU - Chauhan, Deepa
AU - Chauhan, Manisha
AU - Christian, Alice
AU - Cohen, Paul
AU - Colley, Alison
AU - Crook, Ashley
AU - Cui, James
AU - Courtney, Eliza
AU - Cummings, Margaret
AU - Dawson, Sarah-Jane
AU - deFazio, Anna
AU - Delatycki, Martin
AU - Dickson, Rebecca
AU - Dixon, Joanne
AU - Edwards, Stacey
AU - Farshid, Gelareh
AU - Fellows, Andrew
AU - Fenton, Georgina
AU - Field, Michael
AU - Flanagan, James
AU - Fong, Peter
AU - Forrest, Laura
AU - Fox, Stephen
AU - French, Juliet
AU - Friedlander, Michael
AU - Gaff, Clara
AU - Gattas, Mike
AU - George, Peter
AU - Greening, Sian
AU - Harris, Marion
AU - Hart, Stewart
AU - Harraka, Philip
AU - Hayward, Nick
AU - Hopper, John
AU - Hoskins, Cass
AU - Hunt, Clare
AU - Jenkins, Mark
AU - Kidd, Alexa
AU - Kirk, Judy
AU - Koehler, Jessica
AU - Kollias, James
AU - Lakhani, Sunil
AU - Lawrence, Mitchell
AU - Lee, Jason
AU - Li, Shuai
AU - Lindeman, Geoff
AU - Lippey, Jocelyn
AU - Lipton, Lara
AU - Lobb, Liz
AU - Loi, Sherene
AU - Mann, Graham
AU - Marsh, Deborah
AU - McLachlan, Sue Anne
AU - Meiser, Bettina
AU - Nightingale, Sophie
AU - O'Connell, Shona
AU - O'Sullivan, Sarah
AU - Ortega, David Gallego
AU - Pachter, Nick
AU - Pang, Jia-Min
AU - Pathak, Gargi
AU - Patterson, Briony
AU - Pearn, Amy
AU - Phillips, Kelly
AU - Pieper, Ellen
AU - Ramus, Susan
AU - Rickard, Edwina
AU - Ragunathan, Abi
AU - Robinson, Bridget
AU - Saleh, Mona
AU - Skandarajah, Anita
AU - Salisbury, Elizabeth
AU - Saunders, Christobel
AU - Saunus, Jodi
AU - Savas, Peter
AU - Scott, Rodney
AU - Scott, Clare
AU - Sexton, Adrienne
AU - Shaw, Joanne
AU - Shelling, Andrew
AU - Srinivasa, Shweta
AU - Simpson, Peter
AU - Taylor, Jessica
AU - Taylor, Renea
AU - Thorne, Heather
AU - Trainer, Alison
AU - Tucker, Kathy
AU - Visvader, Jane
AU - Walker, Logan
AU - Williams, Rachael
AU - Winship, Ingrid
AU - Young, Mary Ann
AU - Zaheed, Milita
AU - Jakubowska, Anna
AU - Khusnutdinova, Elza K.
AU - Kristensen, Vessela N.
AU - Li, Jingmei
AU - Lim, Joanna
AU - Lindblom, Annika
AU - Liu, Jenny
AU - Lophatananon, Artitaya
AU - Mannermaa, Arto
AU - Mavroudis, Dimitrios A.
AU - Mensenkamp, Arjen R.
AU - Milne, Roger L.
AU - Muir, Kenneth R.
AU - Newman, William G.
AU - Obi, Nadia
AU - Panayiotidis, Mihalis I.
AU - Park, Sue K.
AU - Park-Simon, Tjoung-Won
AU - Peterlongo, Paolo
AU - Radice, Paolo
AU - Rashid, Muhammad U.
AU - Rhenius, Valerie
AU - Saloustros, Emmanouil
AU - Sawyer, Elinor J.
AU - Schmidt, Marjanka K.
AU - Seibold, Petra
AU - Shah, Mitul
AU - Southey, Melissa C.
AU - Teo, Soo Hwang
AU - Tomlinson, Ian
AU - Torres, Diana
AU - Truong, Thérèse
AU - van de Beek, Irma
AU - van der Hout, Annemieke H.
AU - Wendt, Camilla C.
AU - Dunning, Alison M.
AU - Pharoah, Paul D.P.
AU - Devilee, Peter
AU - Easton, Douglas F.
AU - James, Paul A.
AU - Spurdle, Amanda B.
PY - 2024/9/5
Y1 - 2024/9/5
N2 - Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.
AB - Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.
KW - Adult
KW - BRCA1 Protein/genetics
KW - BRCA2 Protein/genetics
KW - Breast Neoplasms/genetics
KW - Fanconi Anemia Complementation Group N Protein/genetics
KW - Female
KW - Genetic Predisposition to Disease
KW - Germ-Line Mutation/genetics
KW - Humans
KW - Middle Aged
KW - Mutation, Missense/genetics
KW - Tumor Suppressor Protein p53/genetics
KW - ACMG/AMP
KW - variant classification
KW - BP5
KW - breast cancer
KW - co-observation
KW - genetics
KW - sequencing data
UR - https://www.mendeley.com/catalogue/cff8405e-392f-3c01-8a6f-c74e775dee12/
U2 - 10.1016/j.ajhg.2024.07.004
DO - 10.1016/j.ajhg.2024.07.004
M3 - Article
C2 - 39096911
VL - 111
SP - 2059
EP - 2069
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 9
ER -
