Co-observation of germline pathogenic variants in breast cancer predisposition genes

TY - JOUR

T1 - Co-observation of germline pathogenic variants in breast cancer predisposition genes

T2 - 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 - 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

AU - NBCS Collaborators

N1 - Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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.

U2 - 10.1016/j.ajhg.2024.07.004

DO - 10.1016/j.ajhg.2024.07.004

M3 - SCORING: Journal article

C2 - 39096911

VL - 111

SP - 2059

EP - 2069

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 9

ER -