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
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
medRxiv. 2024 Sep 4:2024.09.04.24313051. doi: 10.1101/2024.09.04.24313051.
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, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of and from 96,691 female breast cancer cases and 303,925 unaffected 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 observed 11,227 and variants, with 6,921 being coding, covering 23.4% of and VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for and 92.2% sensitivity and 86.6% specificity for . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for 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具有不确定的临床意义（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，先前的研究结果表明，病例对照似然比（LRs）在变异分类方面优于优势比。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96,691例女性乳腺癌病例和303,925名未受影响对照的种系测序数据：乳腺癌协会联盟的BRIDGES研究、癌症易感性相关风险估计联盟以及英国生物银行。我们观察到11,227个VUS和变异，其中6,921个为编码变异，涵盖了ClinVar中23.4%的VUS以及19.2%的ClinVar策划（可能）良性或致病性变异。病例对照LR证据与ClinVar对（可能）良性或致病性变异的断言高度一致；对于VUS表现出99.1%的敏感性和95.4%的特异性，对于表现出92.2%的敏感性和86.6%的特异性。这种方法为785个未分类变异提供了病例对照证据，可作为临床分类的重要依据。
