dissertationGenetic testing for pathogenic variants resulting in increased breast cancer susceptibility is a useful tool in the clinic when determining the medical management of individuals with family histories of breast cancer. Once a pathogenic variant has been identified, healthy biological relatives can be testing for the pathogenic variant, and carriers can benefit from preemptive medical or surgical risk reduction strategies. Eligibility for genetic testing can be complicated; incorporating ages of onset for cancer diagnosis (≤ 50 years, for most cancers), cancer incidence across multiple generations, or biological relatives with multiple diagnoses of primary cancers. Recent advancements in technology, notably next-generation sequencing (NGS) applications in the clinic, have allowed the detection of pathogenic variants in a selection or panel of genes. This increased clinical sensitivity has increased the ability to identify those at increased risk for cancer, as well as the need to understand the genes and variants involved. Missense substitutions constitute an appreciable fraction of the burden of pathogenic variants, but are difficult to interpret. Many missense analysis programs have been developed as tools to estimate the deleteriousness of variants. Gene panels for cancer susceptibility include genes with differing levels of associated risk. For breast cancer panels, the high-risk genes include BRCA1, BRCA2, PALB2, and TP53. Carriers of pathogenic variants in high-risk breast cancer susceptibility genes have clear guidelines for clinicians. In order to determine the percentage of women impacted by pathogenic variants in moderate-risk breast cancer genes, variants in nine moderate-risk breast cancer susceptibility genes from previously published studies were graded for severity via frequency, protein location, and in silico predictions from Align-GVGD, MAPP, CADD, and Polyphen-2. Potentially pathogenic rare variants were grouped until an acceptable stratification for variants of uncertain significance (VUS) was established. We observed that 7.5% of early-onset breast cancer cases- versus 2.4% controls, were estimated to carry a medically actionable variant in at least one of the nine moderate-risk breast cancer genes. Genes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) susceptibility have been shown to play a role in pancreatic cancer susceptibility. Germline genetic testing of pancreatic cancer cases could be beneficial for at-risk relatives with pathogenic variants in established HBOC and CRC genes. In pancreatic cancer cases ascertained at the Huntsman Cancer Hospital, but unselected for family history, 7.6-8.5% carried a variant that would alter the screening recommendations for at-risk relatives. A meta-analysis including additional published studies revealed that approximately 11.9% of unselected pancreatic cancer cases carry a pathogenic variant in HBOC or CRC susceptibility genes. The inclusion of both HBOC and CRC susceptibility genes in a panel test for pancreatic cancer cases finds a high enough percentage of carriers to rationalize genetic testing of these patients for HBOC and CRC susceptibility
