对超过40万名女性的分析为BRCA1和BRCA2基因变异分类提供了病例对照证据。
Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.
作者信息
Zanti Maria, O'Mahony Denise G, Parsons Michael T, Dorling Leila, Dennis Joe, Boddicker Nicholas J, Chen Wenan, Hu Chunling, Naven Marc, Yiangou Kristia, Ahearn Thomas U, Ambrosone Christine B, Andrulis Irene L, Antoniou Antonis C, Auer Paul L, Baynes Caroline, Bodelon Clara, Bogdanova Natalia V, Bojesen Stig E, Bolla Manjeet K, Brantley Kristen D, Camp Nicola J, Campbell Archie, Castelao Jose E, Cessna Melissa H, Chang-Claude Jenny, Chen Fei, Chenevix-Trench Georgia, Conroy Don M, Czene Kamila, De Nicolo Arcangela, Domchek Susan M, Dörk Thilo, Dunning Alison M, Eliassen A Heather, Evans D Gareth, Fasching Peter A, Figueroa Jonine D, Flyger Henrik, Gago-Dominguez Manuela, García-Closas Montserrat, Glendon Gord, González-Neira Anna, Grassmann Felix, Hadjisavvas Andreas, Haiman Christopher A, Hamann Ute, Hart Steven N, Hartman Mikael B A, Ho Weang-Kee, Hodge James M, Hoppe Reiner, Howell Sacha J, Jakubowska Anna, Khusnutdinova Elza K, Ko Yon-Dschun, Kraft Peter, Kristensen Vessela N, Lacey James V, Li Jingmei, Lim Geok Hoon, Lindström Sara, Lophatananon Artitaya, Luccarini Craig, Mannermaa Arto, Martinez Maria Elena, Mavroudis Dimitrios, Milne Roger L, Muir Kenneth, Nathanson Katherine L, Nuñez-Torres Rocio, Obi Nadia, Olson Janet E, Palmer Julie R, Panayiotidis Mihalis I, Patel Alpa V, Pharoah Paul D P, Polley Eric C, Rashid Muhammad U, Ruddy Kathryn J, Saloustros Emmanouil, Sawyer Elinor J, Schmidt Marjanka K, Southey Melissa C, Tan Veronique Kiak-Mien, Teo Soo Hwang, Teras Lauren R, Torres Diana, Trentham-Dietz Amy, Truong Thérèse, Vachon Celine M, Wang Qin, Weitzel Jeffrey N, Yadav Siddhartha, Yao Song, Zirpoli Gary R, Cline Melissa S, Devilee Peter, Tavtigian Sean V, Goldgar David E, Couch Fergus J, Easton Douglas F, Spurdle Amanda B, Michailidou Kyriaki
机构信息
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
出版信息
Nat Commun. 2025 May 25;16(1):4852. doi: 10.1038/s41467-025-59979-6.
Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.
临床基因检测可识别导致遗传性癌症的变异，这些信息用于风险评估和临床管理。不幸的是，所识别出的一些变异的临床意义尚不确定（VUS），这使得患者管理变得复杂。病例对照数据是用于对VUS进行分类的一种证据类型。作为种系突变等位基因解释循证网络（ENIGMA）分析工作组的一项举措，我们分析了来自三项研究的96691例女性乳腺癌病例和302116例对照的BRCA1和BRCA2种系测序数据：乳腺癌协会联盟的BRIDGES研究、癌症易感性相关癌症风险评估联盟以及英国生物银行。我们观察到11207个BRCA1和BRCA2变异，其中6909个为编码变异，涵盖了ClinVar中23.4%的BRCA1和BRCA2 VUS以及19.2%的ClinVar整理的（可能）良性或致病性变异。病例对照似然比（ccLR）证据与ClinVar对（可能）良性或致病性变异的断言高度一致；BRCA1的敏感性为99.1%，特异性为95.3%；BRCA2的敏感性为93.3%，特异性为86.6%。这种方法为787个未分类变异提供了病例对照证据；其中包括579个具有强或中度良性证据的变异以及10个具有强致病性证据的变异，其ccLR证据足以改变临床分类。
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