Are changes of unknown clinical significance in the genome related to signaling pathways in breast cancer cases?

Breast cancer is a public health problem worldwide. While breast cancer is the most common cancer among women, it ranks first in cancer-related deaths in women. Like all cancers, breast cancer is a genetic disease. However, it is not always hereditary. The most important genes known to be responsible for hereditary breast cancer are known as BRCA1 and BRCA2. Women with mutations in these genes have an increased risk of developing breast and ovarian cancer. Other genes known to cause breast cancer are ATM, BARD1, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, TP53, MSH6, CDH1, HER-2/neu, RAS, AKT1, EIF-4E, Cyclin-D1 (CCND1), Cyclin-E (CCNE1), c- MYC, c-FOS, AR, ATM, BARD1, BRIP1, CDH1, CHEK2, DIRAS3, NBN, PALB2, RAD50, STK11, TP53 and PTEN. The most commonly used diagnostic method in breast cancer mutation analysis today is the next generation sequencing, as it is fast, reliable and inexpensive. By using the next generation sequencing, clinical exome analysis can also be performed in addition to whole genome and whole exome sequencing. Clinical exome sequencing screens all known genes clinically associated with diseases. With this approach, while new variants that may cause disease can be found, the discovery of new genes that may be responsible for the disease is not possible. However, it is a more effective approach to give results to the patient and not to waste time with very large data. Classification of variants obtained after next generation sequencing has a very important role in the understanding and interpretation of clinical molecular tests. Databases and published literature are used when classifying and reporting a variant. The variants in the gene known to be responsible for any disease, including cancer, have been classified in the "American College of Medical Genetics and Genomics" (ACMG) guideline, making it a guide that everyone can use objectively and impartially. According to the ACMG report, in the identification of variants in genes associated with Mendelian diseases; It is recommended to use the terminology "pathogenic", "likely pathogenic", "benign", "likely benign" and "uncertain significance". Variants that are not included in the classification of benign and pathogenic, that is, variants that are not associated with a certain clinic, are considered as "unknown clinical significance" (VUS) and complicates the evaluation of the disease. At this point, it is recommended that this variant be re-evaluated after a while, together with the developing technology and functional studies. Since the databases are constantly updated, a variant of "unknown clinical significance" may gain meaning after a while. In this thesis presented, the relationship of VUS obtained after clinical exome sequencing of 25 patients with breast cancer was investigated. As a result; it has been thought that variants in the MUC6 and ZNF141 genes may cause breast cancer. However, the insufficient number of patients and the inability to show this functional relationship are considered as limitations of this study. The present study will lead to different studies by demonstrating the segregation of the genes identified in the affected families and conducting more detailed studies.