BRCA2的双等位生殖细胞突变发生在罕见的小儿病Fanconi贫血（FA）的FA-D1亚型中，其在临床上表现为先天畸形和早期发生恶性肿瘤的高倾向性。收集了96例携带BRCA2的双等位突变的FA-D1患者的临床和遗传数据，并用这些数据制定了一种基于BRCA2特定突变的新的癌症风险预测评分系统。该评分系统考虑了相对于BRCA2的外显子11编码与RAD51重组酶相互作用的主要位点的移码/终止和错义突变的位置，并使用MaxEnt和HBond剪接评分来分析潜在的剪接位点扰动。在确定了BRCA2突变的75名FA-D1患者中，66名患者发展了102个恶性肿瘤，每个个体的独立肿瘤数在1到3个之间。周围胚胎瘤出现的中位数年龄为1.0岁，血液恶性肿瘤的中位数为1.8岁，中枢神经系统肿瘤的中位数为2.7岁。接受治疗的患者比未接受治疗的患者存活时间更长。使用我们的新型评分系统，我们可以在FA-D1患者中区分出三个不同的癌症风险组：第一组患者在1.3岁（n=36，95% CI 0.9-1.8）的中位年龄出现首次恶性肿瘤，第二组在2.3岁（n=17，95% CI 1.4-4.4）的中位年龄出现首次恶性肿瘤，第三组在23.0岁（n=22，95% CI 4.3-n/a）的中位年龄出现首次恶性肿瘤。因此，这种评分系统首次允许仅基于BRCA2基因的突变类型和位置预测FA-D1患者的癌症发生。© 作者（们）2023。由牛津大学出版社发表。版权所有，未经许可请勿复制。请通过电子邮件联系：journals.permissions@oup.com。

Biallelic germline mutations in BRCA2 occur in the FA-D1 subtype of the rare pediatric disorder, Fanconi anemia (FA), characterized clinically by congenital abnormalities and a high propensity to develop malignancies early in life. Clinical and genetic data from 96 FA-D1 patients with biallelic BRCA2 mutations were collected and used to develop a new cancer risk prediction score system based on the specific mutations in BRCA2. This score takes into account the location of frameshift/stop and missense mutations relative to exon 11 of BRCA2, which encodes the major sites for interaction with the RAD51 recombinase, and uses the MaxEnt and HBond splicing scores to analyze potential splice site pertubations. Among 75 FA-D1 patients with ascertained BRCA2 mutations, 66 patients developed 102 malignancies, ranging from one to three independent tumors per individual. The median age at the manifestation of peripheral embryonal tumors was 1.0, of hematologic malignancies 1.8, and of CNS tumors 2.7 years, respectively. Patients who received treatment lived longer than those without. Using our novel scoring system, we could distinguish three distinct cancer risk groups among FA-D1 patients: in the first, patients developed their initial malignancy at a median age of 1.3 years (n = 36, 95% CI 0.9-1.8), in the second group at 2.3 years (n = 17, 95% CI 1.4-4.4) and in the 3rd group at 23.0 years (n = 22, 95% CI 4.3-n/a). Therefore, this scoring system allows, for the first time, to predict the cancer manifestation of FA-D1 patients simply based on the type and position of the mutations in BRCA2.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.