Evaluation of Pathogenic and Likely Pathogenic Variants Detected in the Cases whom Clinical Exome Sequencing were Performed due to Cancer and Familial Cancer Risk and Association with the Clinic

The developments in genetics and bioinformatics, especially the improvements in genome sequencing technologies, have increased the importance of genetics in cancer pathogenesis and determination of cancer predisposition. However, the diagnosis is still below 50% with exome sequencing. The reevaluation of sequence analysis may increase the probability of diagnosis. This study is retrospective, descriptive, and observational. The clinical exome sequence (CES) data of 23 cases diagnosed with cancer or familial cancer predisposition were included in the study. Cancer-related gene variations in the CES analysis were classified as pathogenic, likely pathogenic, and variant of unknown significance (VUS) according to the American College of Medical Genetics and Genomics (ACMG) criteria. Benign and likely benign variants were not included in the study. These variants were reanalyzed after approximately one year and associated with the clinics. Twelve cases had breast pathology, four had ovarian cancer, one had lung, one had prostate, and five had a family history of cancer. In the first classification of CES data, 26 (32.50%) likely pathogenic/pathogenic variants and 54 VUS were found. The structural distribution of variants is four deletions, four duplications, and 72 SNPs. Eight cases had no likely pathogenic/pathogenic variant. Six of these cases had breast pathology, and the other two had a family history of cancer. Most variants were found in the protooncogenes, tumor suppressor genes, and DNA repair genes. The pathogenicity of fifteen variants (18.75%) changed in the reanalysis. A single variant with increased pathogenicity (BRCA2 gene 23. exon c.9097dup) was detected. Six variants were classified as likely pathogenic, and two were classified as pathogenic in the first analysis and reclassified as VUS. Six of the 54 variants evaluated as VUS at the initial evaluation were reclassified as likely benign/ benign at the subsequent analyses. When associated with patient clinics, while there was no significant change in the classical cancer susceptibility genes, the change was more apparent in moderate or rare variants. Current guidelines recommend periodically reviewing the status of variants in CES and NGS data in light of the emerging data. By adapting to new information quickly and implementing new data in the analyses, we can improve the accuracy and relevance of our findings. Ultimately, we can provide more data to make targeted decisions about patient treatment. Our research findings indicate that making treatment decisions based on repeated analyses can benefit the patient. This approach can be considered as part of the comprehensive treatment plan. The necessity and benefits of reanalyzing should be addressed to patients in genetic counseling sessions.