Expert consensus on population-based BRCA germline mutation screening in China (2024 edition)

doi:10.19401/j.cnki.1007-3639.2024.02.010

Abstract

Abstract:

Germline mutations in BRCA genes (including BRCA1/2) are the major risk factors for hereditary tumors including breast and ovarian cancer. Population based BRCA gene screening, particularly in high-risk individuals with a family history of cancer, can play a preventive role by reducing mortality and societal impact of these genetic diseases. Recent years have witnessed the increasing accessibility of BRCA germline mutation testing based on next generation sequencing technology. To further standardize the workflow for BRCA germline mutation screening in the Chinese population, a consensus development group was established by the China Anti-Cancer Association Tumor Biomarker Professional Committee and the Shanghai Anti-Cancer Association Tumor Biomarker Professional Committee. Using an evidence-based approach and building upon literature reviews, the group formulated preliminary recommendations with quality assessments and evidence synthesis regarding common concerns in the process of BRCA germline testing in the population, including screening scenarios, technical approaches, quality control, result interpretation and reporting, as well as genetic counseling. Through multidisciplinary discussions and Delphi questionnaire survey "expert consensus on population-based BRCA germline mutation screening in China (2024 edition)" was developed after summarization and revision. This consensus aims to provide evidence-based guidance and regulatory foundations for BRCA germline mutation screening in the Chinese population and lay the groundwork for further guideline development.

Key words: Expert consensus, BRCA1, BRCA2, Homologous recombination, Mutation screening, Next-generation sequencing, Germline mutation

CLC Number:

R730.1

China Anti-Cancer Association Tumor Biomarker Professional Committee, Shanghai Anti-Cancer Association Tumor Biomarker Professional Committee. Expert consensus on population-based BRCA germline mutation screening in China (2024 edition)[J]. China Oncology, 2024, 34(2): 220-238.

Figures/Tables 11

临床问题	证据级别
临床问题	1级	2级	3级	4级	5级
疾病或事件的发生率	在疾病或事件发生的当地和即刻进行的随机抽样调查（或人口普查）	与事发地情况有可比性的若干其他情形下进行抽样调查的系统综述	当地的非随机样本调查	病例系列	无
疾病筛查	随机试验的系统综述	随机试验	非随机对照队列或随访研究	病例系列、病例对照研究或历史对照研究	基于机制的推理
诊断或监测的准确性	采用同一参考标准并应用盲法的若干横断面研究的系统综述	采用同一参考标准并应用盲法的单一横断面研究	非连续收集的数据或采用非同一参考标准的研究	病例对照研究；或低质量的采用不独立于试验方法的参考标准的研究	基于机制的推理
预后或自然病程	起始队列研究的系统综述	起始队列研究	队列研究或随机试验的对照组	病例系列、病例对照研究或低质量的前瞻性队列研究	无
干预效果（治疗获益）	随机试验或单病例随机对照试验的系统综述	随机试验或效果显著的观察性研究	非随机对照队列或随访研究	病例系列、病例对照研究或历史对照研究	基于机制的推理
治疗常见危害	随机试验的系统综述，巢式病例对照研究的系统综述，针对被研究患者的单病例随机对照试验，或显著效果的观察性研究	单个随机试验或效果显著的观察性研究	非随机对照队列或随访研究（上市后监督），研究样本量应足以判断某危害为常见或罕见危害，随访时间应足以确定长期危害	病例系列病例对照研究或历史对照研究	基于机制的推理
治疗少见危害	随机试验或单病例随机对照试验的系统综述	随机试验或效果显著的观察性研究	非随机对照队列或随访研究（上市后监督），研究样本量应足以判断某危害为常见或罕见危害，随访时间应足以确定长期危害	病例系列病例对照研究或历史对照研究	基于机制的推理

研究类型	纳入人群	主要结果	OCEBM 证据等级
系统综述^[63]	NCCN等32款指南	对于遗传性乳腺癌风险人群，应当在遗传咨询后进行BRCA胚系突变检测（NCCN）。由于遗传测试的结果可能具有治疗意义，应当尽早开展检测（ESMO）。基于人群的筛查计划可以发现更多的乳腺癌患者（美国1.91%，英国1.86%）并降低乳腺癌死亡病例数（美国每百万妇女367例、英国每百万妇女523例）。	1级
系统综述^[64]	USPSTF等15款指南	具有卵巢癌家族史的人群，在遗传咨询后进行BRCA胚系突变检测（USPSTF）。BRCA胚系突变时，必须传达并采取适当的临床遗传转诊措施，以使更多的家庭成员获得早期检测和癌症预防的机会。	1级
系统综述^[18]	15 256例（72项研究）	中国人群中致病性的BRCA胚系突变总体携带率为0.29% ~ 1.10%，高于日本、韩国等已经充分筛查的东亚人群（0.26%），约为需进行常规筛查的犹太人群的一半。	3级
病例系列^[65]	1 184例	使用基于肿瘤家族史的BRCA胚系突变筛查策略导致超过50%的致病性突变被漏检	4级
系统综述^[22]	SEER等29种决策模型	基于人群的BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2胚系突变筛查策略相比于基于临床标准/癌症家族史的筛查策略具有更好的成本效益比，增量成本效益比提高2.8倍（英国）及1.1倍（美国）。	1级
横断面研究^[23]	261例（含59例男性）	进行筛查不会增加患者担忧、回避性思维、以及心理负担关。非携带者在测试后癌症相关担忧显著下降（P<0.001）。年轻的（年龄<50岁）女性致病性突变携带者出现癌症相关担忧（P<0.05），但在测试后12个月回到测试前基线水平。突变携带者更积极的参加预防性筛查及干预。	4级
横断面研究^[24]	167例	在BRCA胚系突变筛查后的4年内，74%的女性在检测后没有因检测结果产生额外的心理压力，51%的女性表示与家人沟通及家庭支持方面得到了正向帮助。	4级

研究类型	纳入人群	主要结果	OCEBM 证据等级
病例对照^[10]	63 828例肿瘤患者及37 086例对照	BRCA1突变阳性人群，女性乳腺癌、卵巢癌和胰腺癌的发病分险分别增加16.1（95% CI：7.1 ~ 36.7）倍、75.6（95% CI：31.6 ~ 180.6）倍和12.6（95% CI：3.7 ~ 42.8）；BRCA2突变阳性人群，女性乳腺癌、男性乳腺癌、卵巢癌、胰腺癌和前列腺癌的发病分险分别增加10.9（95% CI：7.0 ~ 17.1）倍、67.9（95% CI：19.2 ~ 239.8）倍、11.3（95% CI：5.6 ~ 23.0）倍、10.7 （95%CI 5.1 ~ 22.6）倍和4.0 （95% CI：2.5 ~ 6.5）倍。	4级
系统综述^[41]	18 195例（10项研究）	BRCA1突变携带者70岁时乳腺癌累积风险为57%（95% CI：47% ~ 66%），卵巢癌累积风险为40%（95% CI：35% ~ 46%）；BRCA2突变携带者70岁时乳腺癌累积风险为49%（95% CI：40% ~ 57%），卵巢癌累积风险为18%（95% CI：13% ~ 23%）。	1级
系统综述^[44]	4 422个家系（7项研究）	BRCA1突变携带者70岁时乳腺癌外显率为64.6%（95% CI：59.5% ~ 69.4%），卵巢癌为48.3%（95% CI：38.8% ~ 57.9%）；BRCA2突变携带者70岁时乳腺癌外显率为61.0%（95% CI：48.1% ~ 72.5%），卵巢癌风险为20.0%（95% CI：13.3% ~ 29.0%）。	1级
前瞻性队列研究^[42]	978例BRCA1突变携带者和909例 BRCA2突变携带者	BRCA1突变携带者70岁时乳腺癌累积风险为60.0%（95% CI：44.0% ~ 75.0%），卵巢癌的风险为59.0%（95% CI：43.0% ~ 76.0%）；BRCA2突变携带者，相应的乳腺癌风险为55.0%（95% CI：41.0% ~ 70.0%），卵巢癌风险为16.5%（95% CI：7.5% ~ 34.0%）。	2级
队列研究^[43]	7 618个携带BRCA1或BRCA2突变的家系	BRCA1突变与男性乳腺癌（RR=4.30；95% CI：1.09 ~ 16.96）、胰腺癌（RR=2.36；95% CI：1.51 ~ 3.68）和胃癌（RR=2.17；95% CI：1.25 ~ 3.77）的风险相关。BRCA2 突变与男性乳腺癌（RR=44.00；95% CI：21.30 ~ 90.90）、胃癌（RR=3.69；95% CI：2.40 ~ 5.67）、胰腺癌（RR=3.34；95% CI：2.21 ~ 5.06）和前列腺癌（RR=2.22；95% CI：1.63 ~ 3.03）的风险相关。BRCA1携带者到80岁时的患癌绝对风险从的男性乳腺癌的0.40%到胰腺癌的2.50%不等，BRCA2携带者的患癌风险从胰腺癌的约2.50%到前列腺癌的27.0%不等。	3级

临床问题	推荐意见	推荐强度
应当在什么场景下开展人群BRCA胚系突变筛查?	BRCA突变相关肿瘤的遗传高风险人群建议进行基因检测。暂未确定为高风险人群的个体建议在自愿原则下完成基因检测	普通推荐
	BRCA基因筛查推荐在18岁以后进行，可综合考虑家族史、个人偏好、伦理因素以及是否进行生殖干预来决定筛查时间	强推荐
推荐以什么样的工作流程进行人群BRCA筛查?	筛查的工作流程应包括检测前咨询、基因检测及检测后咨询。基因检测应基于检测前咨询结果展开	强推荐
如何进行检测前的遗传咨询?	BRCA胚系突变检测前需进行遗传咨询，在充分尊重受检者及其家属隐私的情况下进行个人及家族史收集及家系图绘制，个体遗传风险评估，沟通检测目的与方法、可能的检测结果，并签署知情同意书	强推荐
在人群中进行BRCA胚系突变筛查应该使用何种分子生物学技术并进行质量控制?	对尚未明确家系基因型的人群优先使用NGS进行筛查，如发现潜在LGR变异，使用MLPA确认。对已明确家系基因型的人群仍建议使用NGS进行检测以尽可能多地获取BRCA基因突变及拷贝数变异信息，也可使用Sanger测序确证变异携带情况。对具有明显家族史且NGS筛查结果阴性的人群使用MLPA排查BRCA LGR变异，并可进行其他易感基因筛查	强推荐
	基因检测全过程应当实施严格的质量保证措施。遵循“人、机、料、法、环”原则，设置基因检测程序和质量控制体系，确保检测结果有效、准确、可靠	强推荐
如何对检测到的突变进行规范化地命名、解读与报告?	推荐使用HGVS命名法作为检出BRCA突变的命名原则，规范基因变异的命名。BRCA胚系变异按照风险程度由低到高可分为良性（benign，1类）、疑似良性（likely benign，2类）、意义未明（uncertain significance，3类）、疑似致病性（likely pathogenic，4类）及致病性（pathogenic，5类），受检者的总体BRCA变异状态应为其所有BRCA1/2基因变异中风险程度最高的类别	强推荐
	推荐依照ACMG和AMP序列变异解读标准和指南，进行BRCA胚系变异的致病性分类。对于其中人群数据库的应用，除常用的gnomAD、ExAC、ESP或千人基因组计划（1000 Genome Project）外，还应纳入“华表”数据库（“HUABIAO” Whole-Exome Public Database）等本地数据	强推荐
	报告内容应至少包括以下部分：受检人信息、样本信息、检测结果、参考范围、基因变异分类的详细解释、检测方法和覆盖区域、检测方法的局限性、发布报告的实验室标识与联系信息、以及检测人及审核者签名。受检人信息应当包括姓名、性别、年龄、唯一标识号及肿瘤家族史情况
如何解读所检测到BRCA胚系突变的临床意义，并据此进行检测后遗传咨询?	BRCA胚系突变携带者罹患乳腺癌、卵巢癌、胰腺癌、前列腺癌等恶性肿瘤的风险显著高于普通人群。通过BRCA基因检测可评估受检者及直系亲属将来发生上述肿瘤的风险，从而及早采取系统全面的预防干预策略，并为发病后的患者精准治疗提供分子生物学依据	强推荐
	针对检出BRCA P/LP变异的人群，应给予个体化的风险管理建议，包括BRCA相关肿瘤的定期筛查与监测，必要时可考虑药物预防或手术预防。对于BRCA P/LP携带者的直系亲属，建议进行遗传咨询及相应变异位点的筛查，根据筛查结果进行风险管理	强推荐
	在没有进一步的证据证明该变异的有害性之前，不应根据BRCA基因VUS结果进行风险管理。在条件允许的情况下，可以对受检者家系必要成员进行同位点验证，以增加该变异致病性分类的证据。当VUS的评级出现变化后，应及时告知临床或受检者，并根据结果判断是否需对其健康管理方案进行调整	强推荐
	针对BRCA胚系突变筛查阴性的受检者，需解释说明该检测的局限性，未检出可报告变异并不代表受检者没有发生肿瘤的风险或完全排除存在其他肿瘤易感基因变异的情况，同时还需要说明基于种群变异相关信息所预测的残余风险值	普通推荐
对检测后所获得的样本和数据应当如何管理?	基因信息已经成为一种重要的战略性国家资源。如需对人类遗传资源信息向外国组织、个人及其设立或者实际控制的机构提供或者开放使用的，应当按照国家关于人类遗传资源管理的相关法律法规执行，向主管科学技术行政部门备案并提交信息备份	强推荐

References 69

[1]	JEGGO P A, PEARL L H, CARR A M. DNA repair, genome stability and cancer: a historical perspective[J]. Nat Rev Cancer, 2016, 16(1): 35-42. doi: 10.1038/nrc.2015.4 pmid: 26667849
[2]	NAROD S A, FOULKES W D. BRCA1 and BRCA2: 1994 and beyond[J]. Nat Rev Cancer, 2004, 4(9): 665-676. doi: 10.1038/nrc1431
[3]	DALY M B, PILARSKI R, YURGELUN M B, et al. NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020[J]. J Natl Compr Canc Netw, 2020, 18(4): 380-391. doi: 10.6004/jnccn.2020.0017
[4]	中国医师协会精准治疗委员会乳腺癌专业委员会, 中华医学会肿瘤学分会乳腺肿瘤学组, 中国抗癌协会乳腺癌专业委员会, 等. 中国乳腺癌患者BRCA1/2基因检测与临床应用专家共识(2018年版)[J]. 中国癌症杂志, 2018, 28(10): 787-800. doi: 10.19401/j.cnki.1007-3639.2018.10.011
	Breast cancer Professional Committee of Precision Therapy Committee of Chinese Medical Doctor Association, Breast Cancer Group of Cancer Branch of Chinese Medical Association, Breast Cancer Professional Committee of China Anti-Cancer Association, et al. Expert consensus on BRCA1/2 gene detection and clinical application of breast cancer patients in China (2018 edition)[J]. China Oncol, 2018, 28(10): 787-800.
[5]	中华医学会病理学分会, 国家病理质控中心. BRCA1/2数据解读中国专家共识(2021版)[J]. 中华病理学杂志, 2021, 50(6): 565-571.
	Chinese Medical Association Pathology Branch, National Pathology Quality Control Center. Chinese expert consensus on BRCA1/2 variant interpretation (2021 version)[J]. Chin J Pathol, 2021, 50(6): 565-571.
[6]	《基于下一代测序技术的BRCA1/2基因检测指南(版)》编写组. 基于下一代测序技术的BRCA1/2基因检测指南(2019版)[J]. 中华病理学杂志, 2019, 48(9): 670-677.
	Writing group of guideline on next generation sequencing based BRCA gene testing. Guideline on next generation sequencing based BRCA1/2 testing (2019)[J]. Chin J Pathol, 2019, 48(9): 670-677.
[7]	DONG H, CHANDRATRE K, QIN Y, et al. Prevalence of BRCA1/BRCA2 pathogenic variation in Chinese Han population[J]. J Med Genet, 2021, 58(8): 565-569. doi: 10.1136/jmedgenet-2020-106970
[8]	GROUP O L O E W. The Oxford levels of evidence 2[EB/OL]. [2023-11-10]. https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence.
[9]	HASSETT M J, SOMERFIELD M R, BAKER E R, et al. Management of male breast cancer: ASCO guideline[J]. J Clin Oncol, 2020, 38(16): 1849-1863. doi: 10.1200/JCO.19.03120 pmid: 32058842
[10]	MOMOZAWA Y, SASAI, USUI Y, et al. Expansion of cancer risk profile for BRCA1 and BRCA2 pathogenic variants[J]. JAMA Oncol, 2022, 8(6): 871-878. doi: 10.1001/jamaoncol.2022.0476
[11]	MORAN A, O’HARA C, KHAN S, et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations[J]. Fam Cancer, 2012, 11(2): 235-242. doi: 10.1007/s10689-011-9506-2
[12]	NETWORK N C C. NCCN guidelines version 1.2023. Breast, ovarian, and/or pancreatic cancer genetic assessment[S]. 2023.
[13]	SESSA C, BALMAÑA J, BOBER S L, et al. Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO clinical practice guideline[J]. Ann Oncol, 2023, 34(1): 33-47. doi: 10.1016/j.annonc.2022.10.004
[14]	US PREVENTIVE SERVICES TASK FORCE, OWENS D K, DAVIDSON K W, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US preventive services task force recommendation statement[J]. JAMA, 2019, 322(7): 652-665. doi: 10.1001/jama.2019.10987
[15]	沈松杰, 孙强, 黄欣, 等. 中国女性乳腺癌筛查指南(2022年版)[J]. 中国研究型医院, 2022, 9(2): 6-13.
	SHEN S J, SUN Q, HUANG X, et al. Breast cancer screening guideline for Chinese women (version 2022)[J]. Chin Res Hosp, 2022, 9(2): 6-13.
[16]	国家卫生健康委员会. 卵巢癌诊疗指南(2022年版)[S]. 2022.
	The National Health Commission. Diagnosis and treatment guidelines for ovarian cancer (2022 edition)[S]. 2022.
[17]	NELSON H D, HUFFMAN L H, FU R W, et al. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the US preventive services task force[J]. Ann Intern Med, 2005, 143(5): 362-379. doi: 10.7326/0003-4819-143-5-200509060-00012
[18]	LEI H J, ZHANG M, ZHANG L Y, et al. Overview on population screening for carriers with germline BRCA mutation in China[J]. Front Oncol, 2022, 12: 1002360. doi: 10.3389/fonc.2022.1002360
[19]	DALY M B, PAL T, BERRY M P, et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2021, 19(1): 77-102. doi: 10.6004/jnccn.2021.0001
[20]	GABAI-KAPARA E, LAHAD A, KAUFMAN B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2[J]. Proc Natl Acad Sci U S A, 2014, 111(39): 14205-14210. doi: 10.1073/pnas.1415979111
[21]	ZHANG L, BAO Y N, RIAZ M, et al. Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis[J]. Genet Med, 2019, 21(9): 1958-1968. doi: 10.1038/s41436-019-0457-6 pmid: 30773532
[22]	MANCHANDA R, PATEL S, GORDEEV V S, et al. Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women[J]. J Natl Cancer Inst, 2018, 110(7): 714-725. doi: 10.1093/jnci/djx265
[23]	WATSON M, FOSTER C, EELES R, et al. Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort[J]. Br J Cancer, 2004, 91(10): 1787-1794. doi: 10.1038/sj.bjc.6602207
[24]	HALBERT C H, STOPFER J E, MCDONALD J, et al. Long-term reactions to genetic testing for BRCA1 and BRCA2 mutations: does time heal women’s concerns?[J]. J Clin Oncol, 2011, 29(32): 4302-4306. doi: 10.1200/JCO.2010.33.1561
[25]	EVANS O, GABA F, MANCHANDA R. Population-based genetic testing for Women’s cancer prevention[J]. Best Pract Res Clin Obstet Gynaecol, 2020, 65: 139-153. doi: 10.1016/j.bpobgyn.2020.02.007
[26]	王剑, 顾卫红, 黄辉, 等. 遗传病二代测序临床检测全流程规范化共识探讨(1): 遗传检测前流程[J]. 中华医学遗传学杂志, 2020, 37(3): 334-338.
	WANG J, GU W H, HUANG H, et al. A consensus on the standardization of the next generation sequencing process for the diagnosis of genetic diseases (1)-procedures prior to genetic testing[J]. Chin J Med Genet, 2020, 37(3): 334-338.
[27]	LIU Y, WANG H L, WANG X, et al. Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort[J]. J Hematol Oncol, 2021, 14(1): 18. doi: 10.1186/s13045-020-01010-0
[28]	LI A, XIE R, ZHI Q H, et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls[J]. Gynecol Oncol, 2018, 151(1): 145-152. doi: 10.1016/j.ygyno.2018.07.024
[29]	ZHANG X F, MAO T B, ZHANG B, et al. Characterization of DNA damage response deficiency in pancreatic cancer patients from China[J]. Cancer Commun, 2022, 42(1): 70-74. doi: 10.1002/cac2.v42.1
[30]	WALLACE A J. New challenges for BRCA testing: a view from the diagnostic laboratory[J]. Eur J Hum Genet, 2016, 24(Suppl 1): S10-S18. doi: 10.1038/ejhg.2016.94
[31]	张学, 季加孚, 徐兵河. 肿瘤遗传咨询(第三版)[M]. 北京: 人民卫生出版社, 2016.
	ZHANG X, JI J F, XU B H. Tumor Genetic Counseling (Third Edition)[M]. Beijing: People’s Health Publishing House, 2016.
[32]	TREPANIER A, AHRENS M, MCKINNON W, et al. Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors[J]. J Genet Couns, 2004, 13(2): 83-114. doi: 10.1023/B:JOGC.0000018821.48330.77 pmid: 15604628
[33]	STROM C M, RIVERA S, ELZINGA C, et al. Development and validation of a next-generation sequencing assay for BRCA1 and BRCA2 variants for the clinical laboratory[J]. PLoS One, 2015, 10(8): e0136419. doi: 10.1371/journal.pone.0136419
[34]	尚红, 王毓三, 申子瑜. 全国临床检验操作规程(第4版)[M]. 北京: 人民卫生出版社, 2016.
	SHANG H, WANG Y S, SHEN Z Y. National Clinical Laboratory Operating Procedures (4th Edition)[M]. Beijing: People's Health Publishing House, 2016.
[35]	国家药品监督管理局. BRCA基因突变检测试剂盒及数据库通用技术要求: YY/T 1865-2022[S]. 北京: 中国标准出版社, 2022.
	The National Medical Products Administration. General technical requirements for BRCA gene mutation detection kit and database: YY/T 1865-2022[S]. Beijing: China Standards Publishing House, 2022.
[36]	RIGGS E R, ANDERSEN E F, CHERRY A M, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)[J]. Genet Med, 2020, 22(2): 245-257. doi: 10.1038/s41436-019-0686-8 pmid: 31690835
[37]	RICHARDS S, AZIZ N, BALE S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. doi: 10.1038/gim.2015.30 pmid: 25741868
[38]	LARSSON N, BORG Å, HODGSON S, et al. European Molecular Genetics Quality Network (EMQN) best practice guidelines for molecular genetics analysis in hereditary breast/ovarian cancer[EB-OL]. (2007-10-25)[2016-09-25]. https://www.emqn.org/emqn/digitalAssets/0/232_EMQNBRCAguidelines0908.pdf.
[39]	ALLELES E-B N F T I O G M. ENIGMA BRCA1/2 gene variant classification criteria[S]. 2017.
[40]	黄辉, 沈亦平, 顾卫红, 等. 临床基因检测报告规范与基因检测行业共识探讨[J]. 中华医学遗传学杂志, 2018, 35(1): 1-8.
	HUANG H, SHEN Y P, GU W H, et al. Discussion on the standard of clinical genetic testing report and the consensus of gene testing industry[J]. Chin J Med Genet, 2018, 35(1): 1-8.
[41]	CHEN S N, PARMIGIANI G. Meta-analysis of BRCA1 and BRCA2 penetrance[J]. J Clin Oncol, 2007, 25(11): 1329-1333. doi: 10.1200/JCO.2006.09.1066
[42]	MAVADDAT N, PEOCK S, FROST D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE[J]. J Natl Cancer Inst, 2013, 105(11): 812-822. doi: 10.1093/jnci/djt095
[43]	LI S, SILVESTRI V, LESLIE G, et al. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants[J]. J Clin Oncol, 2022, 40(14): 1529-1541.
[44]	CHEN J B, BAE E, ZHANG L J, et al. Penetrance of breast and ovarian cancer in women who carry a BRCA1/2 mutation and do not use risk-reducing salpingo-oophorectomy: an updated meta-analysis[J]. JNCI Cancer Spectr, 2020, 4(4): pkaa029. doi: 10.1093/jncics/pkaa029
[45]	VAIL P J, MORRIS B, VAN KAN A, et al. Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases[J]. J Community Genet, 2015, 6(4): 351-359. doi: 10.1007/s12687-015-0220-x
[46]	BREAST CANCER ASSOCIATION CONSORTIUM, MAVADDAT N, DORLING L, et al. Pathology of tumors associated with pathogenic germline variants in 9 breast cancer susceptibility genes[J]. JAMA Oncol, 2022, 8(3): e216744. doi: 10.1001/jamaoncol.2021.6744
[47]	TAI Y C, DOMCHEK S, PARMIGIANI G, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers[J]. J Natl Cancer Inst, 2007, 99(23): 1811-1814. doi: 10.1093/jnci/djm203
[48]	LECARPENTIER J, SILVESTRI V, KUCHENBAECKER K B, et al. Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores[J]. J Clin Oncol, 2017, 35(20): 2240-2250. doi: 10.1200/JCO.2016.69.4935
[49]	EVANS D G R, SUSNERWALA I, DAWSON J, et al. Risk of breast cancer in male BRCA2 carriers[J]. J Med Genet, 2010, 47(10): 710-711. doi: 10.1136/jmg.2009.075176
[50]	NYBERG T, FROST D, BARROWDALE D, et al. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study[J]. Eur Urol, 2020, 77(1): 24-35. doi: 10.1016/j.eururo.2019.08.025
[51]	KAUFMAN B, SHAPIRA-FROMMER R, SCHMUTZLER R K, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation[J]. J Clin Oncol, 2015, 33(3): 244-250.
[52]	DOMCHEK S M, AGHAJANIAN C, SHAPIRA-FROMMER R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy[J]. Gynecol Oncol, 2016, 140(2): 199-203. doi: 10.1016/j.ygyno.2015.12.020
[53]	SWISHER E M, LIN K K, OZA A M, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial[J]. Lancet Oncol, 2017, 18(1): 75-87. doi: S1470-2045(16)30559-9 pmid: 27908594
[54]	MIRZA M R, MONK B J, HERRSTEDT J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[J]. N Engl J Med, 2016, 375(22): 2154-2164. doi: 10.1056/NEJMoa1611310
[55]	AGARWAL N, AZAD A A, CARLES J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial[J]. Lancet, 2023, 402(10398): 291-303. doi: 10.1016/S0140-6736(23)01055-3 pmid: 37285865
[56]	NETWORK N C C. NCCN clinical practice guidelines in oncology-breast cancer (version 4. 2023)[S]. 2023.
[57]	NETWORK N C C. NCCN clinical practice guidelines in oncology-ovarian cancer including fallopian tube cancer and primary peritoneal cancer (version 1. 2023)[S]. 2023.
[58]	NETWORK N C C. NCCN clinical practice guidelines in oncology-pancreatic adenocarcinoma (version 2. 2022)[S]. 2023.
[59]	NETWORK N C C. NCCN clinical practice guidelines in oncology-prostate cancer (version 1. 2023)[S]. 2023.
[60]	MERSCH J, BROWN N, PIRZADEH-MILLER S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing[J]. JAMA, 2018, 320(12): 1266-1274. doi: 10.1001/jama.2018.13152 pmid: 30264118
[61]	ESTERLING L, WIJAYATUNGE R, BROWN K, et al. Impact of a cancer gene variant reclassification program over a 20-year period[J]. JCO Precis Oncol, 2020, 4: PO.20.00020.
[62]	中华人民共和国国务院. 中华人民共和国人类遗传资源管理条例:国务院发[2019]717号(2019-6-10)[EB/OL]. [2023-10-1]. https://www.gov.cn/zhengce/content/2019-06/10/content_5398829.htm.
	The State Council of the People's Republic of China. Regulations of the People's Republic of China on the Management of Human Genetic Resources: State Council Document [2019] No. 717 (2019-6-10)[EB/OL]. [2023-10-1]. https://www.gov.cn/zhengce/content/2019-06/10/content_5398829.htm.
[63]	FORBES C, FAYTER D, KOCK S D, et al. A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer[J]. Cancer Manag Res, 2019, 11: 2321-2337. doi: 10.2147/CMAR
[64]	ECCLES D M, BALMAÑA J, CLUNE J, et al. Selecting patients with ovarian cancer for germline BRCA mutation testing: findings from guidelines and a systematic literature review[J]. Adv Ther, 2016, 33(2): 129-150. doi: 10.1007/s12325-016-0281-1
[65]	KEMP Z, TURNBULL A, YOST S, et al. Evaluation of cancer-based criteria for use in mainstream BRCA1 and BRCA2 genetic testing in patients with breast cancer[J]. JAMA Netw Open, 2019, 2(5): e194428. doi: 10.1001/jamanetworkopen.2019.4428
[66]	PASSAPERUMA K, WARNER E, CAUSER P A, et al. Long-term results of screening with magnetic resonance imaging in women with BRCA mutations[J]. Br J Cancer, 2012, 107(1): 24-30. doi: 10.1038/bjc.2012.204
[67]	PHI X A, SAADATMAND S, DE BOCK G H, et al. Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis[J]. Br J Cancer, 2016, 114(6): 631-637. doi: 10.1038/bjc.2016.32
[68]	METCALFE K, LYNCH H T, GHADIRIAN P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers[J]. J Clin Oncol, 2004, 22(12): 2328-2335. doi: 10.1200/JCO.2004.04.033
[69]	FINCH A P, LUBINSKI J, MØLLER P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation[J]. J Clin Oncol, 2014, 32(15): 1547-1553. doi: 10.1200/JCO.2013.53.2820

问题	情况	分值
同时罹患乳腺癌及卵巢癌的亲属	母亲	10
	兄弟姐妹	7
	二级亲属或三级亲属	5
罹患乳腺癌的亲属	父母	4
	兄弟姐妹	3
	二级亲属或三级亲属	2
	男性亲属	2（额外加分）
乳腺癌患病年龄	20 ~ 29岁	6
	30 ~ 39岁	4
	40 ~ 49岁	2
	围绝经期	2
	双侧乳房患病或多病灶	3
罹患卵巢癌的亲属	母亲	7
	姐妹	4
	二级亲属或三级亲属	3
卵巢癌患病年龄	<40岁	6
	40 ~ 60岁	4
	>60岁	2
前列腺癌患病年龄	<50岁	1
结肠癌患病年龄	<50岁	1

直系亲属发病年龄	年龄	BRCA1评分	BRCA2评分
女性亲属乳腺癌	<30岁	6	5
	30 ~ 39岁	4	4
	40 ~ 49岁	3	3
	50 ~ 59岁	2	2
	≥60岁	1	1
男性乳腺癌	<60岁	5（如果进行BRCA2检测）	8（如果进行BRCA1检测）
	≥60岁	5（如果进行BRCA2检测）	5（如果进行BRCA1检测）
卵巢癌	<60岁	8	5
	≥60岁	5	5
胰腺癌	任何年龄	0	1
前列腺癌	<60岁	0	2
	≥60岁	0	1

风险因素	50岁前发病的罹患乳腺癌亲属	罹患卵巢癌亲属
自己
母亲
姐妹
外祖母
阿姨/姨母
祖母
姑姑
50岁后发病的罹患乳腺癌亲属>2（父方或母方）
男性乳腺癌亲属（任何年龄）
犹太人祖先史

情况	对于有乳腺癌或卵巢癌家族史的人群（包括二级亲属或三级亲属）
罹患乳腺癌的亲属年龄>50岁	3
罹患乳腺癌的亲属年龄<50岁	4
亲属罹患卵巢癌	5
男性乳腺癌亲属	8
犹太人祖先史	4

肿瘤类型	个体情况或年龄节段	筛查方式/预防措施	实施频率
女性乳腺癌	18岁后	乳腺自查	-
	25 ~ 29岁	乳房磁共振成像（magnetic resonance imaging，MRI）检查（MRI不适用时可用乳腺X线检查）	每年1次
	30岁前发生乳腺癌或有家族史	根据临床诊断进行个性化影像学检查	-
	30 ~ 75岁	乳腺X线检查和MRI检查	每年1次
	>75岁	根据个体健康情况进行乳腺健康检查	-
	携带BRCA胚系阳性突变且接受乳腺癌治疗未做双侧乳房切除术的人群	乳腺X线检查和MRI检查	每年1次
男性乳腺癌	35岁后	乳腺检查	半年1次
		考虑乳腺钼靶X线检查	每年1次
	BRCA2阳性突变人群家系中最早发生男性乳腺癌的发病年龄小5 ~ 10岁	乳腺钼靶X线检查和MRI检查	每年1次
卵巢癌	完成生育后 35 ~ 40岁，BRCA2阳性可稍晚进行RRSO	进行预防性输卵管卵巢切除术（risk reducing salpingo-oophorectomy，RRSO）	-
	未选择RRSO 30 ~ 35岁后	进行经阴道超声（transvaginal of ultrasound ，TVUS）检查和CA12-5检测	每年1次
胰腺癌	50岁后或家系中最早发生胰腺癌的发病年龄小5 ~ 10岁	增强磁共振或磁共振胰胆管造影术（magnetic resonance cholangiopancreatography，MRCP）或超声内镜（endoscopic ultrasonography，EUS）	每年1次
前列腺癌	40岁后	直肠指诊、前列腺特异性抗原（prostate specific antigen，PSA）检测	每1 ~ 2年1次
黑色素瘤	BRCA2阳性突变人群	暂无有效筛查手段，可进行适当的皮肤检查并尽量减少紫外线照射。	-