乳腺癌易感基因种系致病变异的共同观察：BRIDGES 测序数据集分析的结果。
Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.
发表日期：2024 Jul 30
作者：
Aimee L Davidson, Kyriaki Michailidou, Michael T Parsons, Cristina Fortuno, Manjeet K Bolla, Qin Wang, Joe Dennis, Marc Naven, Mustapha Abubakar, Thomas U Ahearn, M Rosario Alonso, Irene L Andrulis, Antonis C Antoniou, Päivi Auvinen, Sabine Behrens, Marina A Bermisheva, Natalia V Bogdanova, Stig E Bojesen, Thomas Brüning, Helen J Byers, Nicola J Camp, Archie Campbell, Jose E Castelao, Melissa H Cessna, Jenny Chang-Claude, Stephen J Chanock, Georgia Chenevix-Trench, , J Margriet Collée, Kamila Czene, Thilo Dörk, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Jonine D Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Gord Glendon, Anna González-Neira, Felix Grassmann, Jacek Gronwald, Pascal Guénel, Andreas Hadjisavvas, Lothar Haeberle, Per Hall, Ute Hamann, Mikael Hartman, Peh Joo Ho, Maartje J Hooning, Reiner Hoppe, Anthony Howell, , Anna Jakubowska, Elza K Khusnutdinova, Vessela N Kristensen, Jingmei Li, Joanna Lim, Annika Lindblom, Jenny Liu, Artitaya Lophatananon, Arto Mannermaa, Dimitrios A Mavroudis, Arjen R Mensenkamp, Roger L Milne, Kenneth R Muir, William G Newman, Nadia Obi, Mihalis I Panayiotidis, Sue K Park, Tjoung-Won Park-Simon, Paolo Peterlongo, Paolo Radice, Muhammad U Rashid, Valerie Rhenius, Emmanouil Saloustros, Elinor J Sawyer, Marjanka K Schmidt, Petra Seibold, Mitul Shah, Melissa C Southey, Soo Hwang Teo, Ian Tomlinson, Diana Torres, Thérèse Truong, Irma van de Beek, Annemieke H van der Hout, Camilla C Wendt, Alison M Dunning, Paul D P Pharoah, Peter Devilee, Douglas F Easton, Paul A James, Amanda B Spurdle
来源：
AMERICAN JOURNAL OF HUMAN GENETICS
摘要：
基因变异与另一个基因中解释疾病表现的致病性变异的共同观察已被指定为常用变异分类指南中反对致病性的证据。多个变异管理专家小组根据共识指出，这种证据类型不适用于乳腺癌易感基因变异的分类。对来自 BRIDGES 测序项目的 55,815 名被诊断患有乳腺癌的个体的序列数据进行统计分析，以正式评估联合观察数据对于种系变异分类的效用。我们的分析包括 11 个乳腺癌易感基因的预期功能丧失变异以及 BRCA1、BRCA2 和 TP53 的致病性错义变异。我们评估了在独立性假设下，两个不同基因中致病性变异的共同观察发生的频率是否比预期的多或少。 BRCA1、BRCA2 和 PALB2 中每个基因与其余基因的致病性变异的共同观察频率低于预期。在对诊断年龄、研究设计（基于家庭与基于人口的）和国家进行调整后，这种消耗的证据仍然存在。 BRCA1、BRCA2 或 PALB2 中不确定意义的变异与另一个乳腺癌基因中的致病性变异的共同观察相当于根据似然比进行标准强度分配支持反对致病性的证据，并在错义 BRCA1 和 BRCA2 的重新分类中显示出实用性BRIDGES 中发现的变体。我们的方法适用于评估共同观察作为其他临床环境中变异致病性预测因子的价值，包括 ClinGen 变异管理专家小组制定的基因特异性指南。版权所有 © 2024 美国人类遗传学会。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.