BackgroundFounder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway.MethodsA total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.ResultsThere were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.ConclusionsThe spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway’s largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.

中文翻译：

---

BRCA1 和 BRCA2 突变谱——挪威一家大型癌症遗传学诊所的突变分布更新

背景两种乳腺癌基因 BRCA1 和 BRCA2 的Founder 突变已在许多人群中得到描述，其中包括德系犹太人、波兰人、挪威人和冰岛人。在这些人群中，对具有相关血统的患者进行 Founder 突变检测是一种具有成本效益的方法。4 个挪威 BRCA1 创始人突变于 2001 年通过单倍型定义，占当时 BRCA1 突变携带者的 68%。经过 15 多年的基因检测，需要对挪威 BRCA1 和 BRCA2 突变谱的更新知识。在这项研究中，我们旨在描述挪威最大的遗传性癌症诊所的 BRCA1/2 携带者人群中的突变谱和频率。方法来自 669 个不同家庭的总共 2430 名 BRCA1 携带者，来自 312 个不同家庭的 1092 名 BRCA2 携带者被纳入护理质量研究。按照 ACMG/ENIGMA 标准评估所有变体的致病性。在 AlaMut 和补充数据库中对这些变体进行评估，以确定它们是否已知是其他人群中的创始人突变。结果突变携带者中有 120 种不同的 BRCA1 和 87 种不同的 BRCA2 变体。46% 的注册 BRCA1/2 家族 (454/981) 具有先前报道的挪威创始人突变。大多数 BRCA1/2 突变 (71%) 是罕见的，每个突变只在一两个家族中发现。15% 的 BRCA1 家族和 25% 的 BRCA2 家族具有这些罕见变异之一。之前通过单倍型确认的四个著名的挪威 BRCA1 创始人突变仍然是 BRCA1 携带者中最常见的四个突变，但这些突变占 BRCA1 突变携带者的比例已从 68% 下降到 52%，因此创始人效应是结论挪威最大的癌症遗传学诊所的携带者群体中的 BRCA1 和 BRCA2 突变谱是多种多样的，并且具有比之前描述的更弱的创始人效应。因此，重新测试之前已经通过特定测试/创始人突变测试进行测试的家庭应该是寻找更多突变阳性家庭并可能预防健康亲属癌症的优先策略。但由这些突变引起的 BRCA1 突变携带者的比例已从 68% 下降到 52%，因此创始人效应比之前描述的要弱。结论挪威最大的癌症遗传学诊所携带人群中 BRCA1 和 BRCA2 突变的谱是多样的，并且创始人效应比之前描述的要弱。因此，重新测试之前已经通过特定测试/创始人突变测试进行测试的家庭应该是寻找更多突变阳性家庭并可能预防健康亲属癌症的优先策略。但由这些突变引起的 BRCA1 突变携带者的比例已从 68% 下降到 52%，因此创始人效应比之前描述的要弱。结论挪威最大的癌症遗传学诊所携带人群中 BRCA1 和 BRCA2 突变的谱是多样的，并且创始人效应比之前描述的要弱。因此，重新测试之前已经通过特定测试/创始人突变测试进行测试的家庭应该是寻找更多突变阳性家庭并可能预防健康亲属癌症的优先策略。并且创始人效应比之前描述的要弱。因此，重新测试之前已经通过特定测试/创始人突变测试进行测试的家庭应该是寻找更多突变阳性家庭并可能预防健康亲属癌症的优先策略。并且创始人效应比之前描述的要弱。因此，重新测试之前已经通过特定测试/创始人突变测试进行测试的家庭应该是寻找更多突变阳性家庭并可能预防健康亲属癌症的优先策略。