Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway, and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes. We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes (BRCA1, BRCA2, ERBB2 and TP53) in a homogeneous patient cohort from Bangladesh (n = 52) by using tumor and blood samples. Blood derived targeted sequencing revealed 25.58% (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95% (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions in BRCA2, and missense mutations in BRCA1, BRCA2 and ERBB2 gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting both TP53 (c.322dupG; a novel frameshift insertion) and BRCA1 genes (c.116G > A). 22% of tissue samples had a clinically relevant TP53 mutation. Although the cohort is small, we have found pathogenic mutations to be enriched in BRCA2 (9.30%, 4/43) compare to BRCA1 (4.65%, 2/43). The frequency of germline VUS mutations found to be similar in both BRCA1 (4.65%; 2/43) and BRCA2 (4.65%; 2/43) compared to ERBB2 (2.32%; 1/43). This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.

中文翻译：

---

在种族同质人群中通过靶向测序可操作的乳腺癌基因中的新型突变

基因检测正成为乳腺癌（BC）诊断和治疗途径的重要工具，对于早期发现和预防癌症尤为重要。这项研究的目的是探讨高优先级BC基因的靶向测序的诊断率。在来自孟加拉国（n = 52）的同质患者队列中，我们通过使用肿瘤和血液样本，采用了具有成本效益的针对性强的可操作BC基因（BRCA1，BRCA2，ERBB2和TP53）的靶向测序方法。血液衍生的靶向测序揭示了25.58％（11/43）的临床相关突变（致病性和不确定性变异（VUS）），其中13.95％（6/43）的样品带有致病性突变。我们已经确定并验证了该队列中的五个新的致病性种系突变，分别由BRCA2中的两个移码缺失和BRCA1，BRCA2和ERBB2基因的错义突变组成。此外，我们已经在三个肿瘤样品中鉴定出三个致病突变和一个VUS，包括一个携带致病突变的样品，该突变既影响TP53（c.322dupG；新颖的移码插入）又影响BRCA1基因（c.116G> A）。22％的组织样本具有临床相关的TP53突变。尽管队列很小，但我们发现与BRCA1（4.65％，2/43）相比，BRCA2（9.30％，4/43）富含致病性突变。发现BRCA1（4.65％; 2/43）和BRCA2（4.65％; 2/43）的种系VUS突变频率与ERBB2（2.32％; 1/43）相似。这是该人群中BC易感基因的首次遗传研究，