PDF(Pubmed)
Abstract：
Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with \"conflicting interpretations of its pathogenicity\". Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients\' family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers.
摘要：
乳腺癌基因1(BRCA1)和BRCA2是参与DNA损伤反应和修复的肿瘤抑制基因。BRCA1或BRCA2中的种系致病性或可能的致病性变异体的携带者显著增加了乳腺癌的终生风险。卵巢癌,和其他癌症类型;这种现象被称为遗传性乳腺癌和卵巢癌（HBOC）综合征。BRCA1和BRCA2变异的准确解释不仅对患者的疾病管理很重要，但也为他们的家庭确定预防措施。BRCA1：c.132C>T（p。Cys44=）是ClinVar数据库中记录的同义变体，具有“对其致病性的相互矛盾的解释”。这里,我们报告了我们的临床试验，其中我们在两名无关患者中发现了这种变异，他们都在几年后出现卵巢表现的早期乳腺癌,并且有相关癌症的家族史.Minigene分析显示，这种变化导致外显子3末端的四个核苷酸丢失，导致截短的p.Cys44Tyrfs*5蛋白。逆转录聚合酶链反应使用从患者血液样本中分离的RNA鉴定了两个片段（123和119bp），与小基因测定的结果一致。总的来说，我们将BRCA1分类为：c.132C>T（p。Cys44=）作为致病变体，功能研究证明了这一点，RNA分析,和病人的家族史。通过分析BRCAExchange数据库中记录的变体，我们发现外显子末端的同义变化可能会影响剪接；同时，如果变体位于外显子的中间，当前的计算机工具无法有效地预测剪接变化，或在深内含子区域。未来的研究应该尝试识别影响基因表达和转录后修饰的变异，以提高我们对BRCA1和BRCA2及其相关癌症的理解。
