Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.

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OBJECTIVE: Compared to the general population, patients of Ashkenazi Jewish descent have an increased risk of being genetic carriers for certain diseases, with an overall carrier rate ranging from 1 in 4 to 1 in 5 1 . Therefore, the American College of Obstetricians and Gynecologists (ACOG) strongly recommends this population be offered carrier screening for four conditions: Tay Sachs, Cystic Fibrosis, Familial Dysautonomia, and Canavan Disease 2 . Some experts have advocated for a more comprehensive screening panel, and subsequently, ACOG recognized that screening for the following Jewish Genetic Diseases can be offered to patients: Bloom syndrome, Familial hyperinsulinism, Fanconi anemia, Gaucher disease, Glycogen storage disease type I, Joubert syndrome, Maple syrup urine disease, Mucolipidosis type IV, Niemann-Pick disease, and Usher syndrome 2 . Given the genetic risks inherent in this population, carrier screening programs have been created to test for these founder mutations and have been successful in significantly decreasing the incidence of certain autosomal recessive conditions. Recently, however, with the advent of pan-ethnic, expanded carrier screening, we have the means to identify carriers for a broader array of conditions beyond the fourteen aforementioned 3 . The objective of this study is to assess whether the current screening recommendations are sufficient in diagnosing carrier status in the Ashkenazi Jewish population.DESIGN: Retrospective cohort study. MATERIALS AND METHODS: This was a retrospective chart review. Students at a single institution underwent genetic testing with expanded carrier screening through an outreach program at Rutgers University Hillel in October 2015. All the students were of Jewish descent. The genetic conditions tested in the expanded carrier screening were grouped into the following three categories based on ACOG's 2017 committee opinion regarding carrier screening: the four strongly recommended genetic conditions, the fourteen genetic conditions that can be offered, and the genetic diseases that are not specifically mentioned for screening in this population. The results were then divided according to this categorization.RESULTS: A total of 81 patients were screened. Of these, 36 (44.4%) were found to be carriers of at least one disease. Out of the 36 patients, 28 were found to be a carrier for one disease, 7 for two diseases, and 1 for three diseases, representing 45 total identified mutations. The carrier rate was 7/45 (15.6%) for the four recommended Jewish Genetic Diseases, 20/45 (44.4%) for the fourteen offered conditions, and 25/45 (55.6%) for genetic diseases that were not recommended in this population.CONCLUSIONS: If carrier screening for the Ashkenazi Jewish population was limited to only founder Jewish mutations in fourteen disorders, 44.4% of carriers would not have been identified. Our data supports that individuals of Ashkenazi descent should be offered pan-ethnic, expanded carrier screening.References: 1.