Germline BRCA1 and BRCA2 loss‐of‐function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1 , 52% in BRCA2 . Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806‐2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1 /2 pathogenic variants among Cretans, provides the possibility of cost‐ and time‐efficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level.

中文翻译：

---

在Cretan分离物中的BRCA1和BRCA2种系测试显示出新颖而强大的创始人效应。

生殖系BRCA1和BRCA2功能丧失的变异与乳腺癌和卵巢癌的风险增加相关，全世界报道了5,000多种不同的致病变异。在具有希腊血统的个体中，BRCA1 / 2变异谱是异质的，但具有强大的创始人效应。由于先前研究中来自希腊某些地理区域的患者（如克里特岛）的代表性不足，我们假设孤立的克里特岛人（希腊南部岛民的人口，具有独特的人口，文化和遗传特征）可能会藏有创始人BRCA1 / 2突变。通过NGS或Sanger测序，然后进行MLPA，对总共304位符合NCCN遗传检测标准的Cretan血统的乳腺癌或卵巢癌患者进行了检测。随后进行单倍型分析以研究复发等位基因的潜在创始人效应。总体而言，接受测试的患者中有16.5％（50/304）携带22种不同的病原体。BRCA1中占48％，BRCA2中占52％。三个变体，即BRCA2中的两个变体（Δ外显子12和13和c.7806-2A> T）和BRCA1中的一个变体（c.5492del），构成所有检测到的病原体变体的大约一半（48％），被证明具有创建者效应，所有携带者共享相同的单倍型。值得注意的是，这些变体仅限于克里特岛人，在希腊其他地区尚未发现。克里特人中特定的BRCA1 / 2致病变体的高患病率为筛查克里特人提供了节省成本和时间的可能性。将这些知识整合到当地的公共卫生服务中可能会对癌症的预防产生重大影响，并且可以作为在人群一级实施检测的起点。