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Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

4059 Background: Anal squamous cell carcinoma (ASCC) is associated with significant symptom burden including pain, bleeding, and obstructive symptoms. However, the proportion of patients requiring palliation-directed treatments in ASCC is unknown. Palliation-directed treatments can control and improve symptoms and affect quality of life. We aimed to study trends, factors, and outcomes associated with utilization of palliation-directed treatment in ASCC. Methods: Using the National Cancer Database (NCDB), adult patients with stage II-IV ASCC diagnosed 2004-2015 were identified and stratified by receipt of palliation-directed treatments. Using chi-square test and logistic regression, we evaluated the associations of demographic, clinical, and pathological factors with palliation-directed treatment utilization. Results: Out of 17,988 ASCC patients in this study, palliation-directed treatments were used by 504 patients (2.8%) with stages II-IV ASCC as first line treatment. Two percent received palliation-directed surgery, chemotherapy, and radiotherapy, 0.3% received pain management, and 0.4% utilized combination therapy approach. On univariable analysis, palliation-directed treatments were associated with older age, lower income level ( p=0.004), Medicare insurance, and higher comorbidity score ( all other p