TY  - JOUR
AU  - Davidson, Aimee L
AU  - Michailidou, Kyriaki
AU  - Parsons, Michael T
AU  - Fortuno, Cristina
AU  - Bolla, Manjeet K
AU  - Wang, Youqing
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  - 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  - 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
TI  - Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.
JO  - The American journal of human genetics
VL  - 111
IS  - 9
SN  - 0002-9297
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2024-01588
SP  - 2059-2069
PY  - 2024
N1  - 2024 Sep 5;111(9):2059-2069
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  - ACMG/AMP (Other)
KW  - BP5 (Other)
KW  - breast cancer (Other)
KW  - co-observation (Other)
KW  - genetics (Other)
KW  - sequencing data (Other)
KW  - variant classification (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39096911
DO  - DOI:10.1016/j.ajhg.2024.07.004
UR  - https://inrepo02.dkfz.de/record/292080
ER  -