Incidence of concurrent pathogenic variants in <i>BRCA1</i> breast cancer patients.

Abstract

10586 Background: Over the years, advancements in genetic testing have led to an expansion in the number of detectable mutations. This progress has enabled the identification of patients with pathogenic genetic variants, allowing for the implementation of tailored cancer screening strategies. For patients with breast cancer or high risk of breast cancer, there are advocates for comprehensive expanded genetic testing panels while others prefer to only perform selective testing for genes associated with breast cancer. The goal of this study was to determine how often patients with BRCA1 pathogenic variants have additional mutations picked up on panel tests and whether they are clinically significant. Methods: We used the Myriad Collaborative Research Registry to access de-identified information on breast cancer patients with BRCA1 variants. We looked at the data collected from individuals that were tested for mutations in 26 or more genes. We identified the most commonly mutated genes that are found in patients with BRCA1 mutations. For this study, the term deleterious is equivalent to pathogenic/likely pathogenic. Results: Among breast cancer patients who underwent expanded panel testing for at least 26 genes, 10,250 individuals were identified to carry deleterious mutations. Of these, 400 patients had deleterious mutations in two or more genes. Within this subgroup, 184 individuals had deleterious BRCA1 mutations along with at least one additional pathogenic mutation. Table 1 lists the most frequently mutated additional genes in patients with BRCA1 mutations in our dataset. The most common pathogenic mutations that co-occur with BRCA1 mutations were found in MUTYH (31.5%), CHEK2 (12.5%) , BRCA2 (12.5%), and ATM (11.4%). One patient had deleterious mutations in BRCA1 and two additional genes ( MUTYH and BRIP1 ). Conclusions: Our data underscores the importance of evaluating patients for additional gene mutations. Extensive evidence demonstrates that certain pathogenic genes increase the risk of specific cancers. Restricting genetic testing to a targeted panel of breast cancer-associated genes may overlook other pathogenic genes that could predispose these individuals to additional malignancies. For instance, identifying pathogenic mutations in PMS2 , in addition to BRCA1 , could lead to meaningful alterations in clinical management. Further research is essential to investigate the clinical significance of co-occurring genetic variants, particularly those involving BRCA1 and other high-risk genes. Most commonly identified concurrent pathogenic genes in BRCA1 breast cancer. Concurrent pathogenic gene Count MUTYH 58 (31.5%) CHEK2 23 (12.5%) BRCA2 23 (12.5%) ATM 21 (11.4%) BRIP1 16 (8.7%) PALB2 8 (4.3%) PMS2 8 (4.3%) NTHL1 6 (3.3%) BARD1 4 (2.2%) Genes in bold are known to be associated with breast cancer.