Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.
Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.
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DOI：
10.1186/bcr1291
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Schmutzler RK
中科院分区：
文献类型：
--
作者：
Wappenschmidt B;Fimmers R;Rhiem K;Brosig M;Wardelmann E;Meindl A;Arnold N;Mallmann P;Schmutzler RK
在BRCA 2基因中经常检测到临床意义未知的未分类变体（UV）。在这项研究中，我们调查了复发性UV S384 F（BRCA 2，外显子10）的潜在致病相关性。共隔离，四名妇女从一个大的亲属（BN 326）患有乳腺癌进行了分析。此外，石蜡包埋的肿瘤从两个病人进行了分析的杂合性丢失。在43，029例索引病例的大数据集中进一步确定了变异与有害突变的共存。对紫外线的性质和位置以及物种间的保护性进行了评价。我们在四名乳腺癌患者中的三名（这三名患者分别在41岁、43岁和57岁时被诊断出）中发现了未分类的变异S384 F。一名患有双侧乳腺癌的妇女（在32岁和50岁时诊断）没有携带这种变异。这两个肿瘤都是S384 F变异体杂合子，因此可以排除野生型等位基因的丢失。Ser 384不位于功能重要性区域，跨物种序列比较显示在人、狗、啮齿动物和鸡BRCA 2同源物中不完全保守。总的来说，在116名患者中检测到了这种变异，其中5名患者同时发生了不同的有害突变。共现、共分离和杂合性缺失的组合似然比为1.4 × 10-8，有利于该变异的中性。我们的数据提供了确凿的证据，S384 F变异不是一种致病突变。
Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 × 10-8 in favour of neutrality of the variant. Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
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