Inherited proclivity for myeloid malignancies is more widespread than previously thought. For a study, researchers examined the whole-exome sequencing data from matched leukemia and skin biopsy samples from 391 adult patients from Beat AML 1.0. They curated 1,547 distinct variations from 228 genes using the 2015 American College of Medical Genetics and Genomics (ACMG) recommendations for variant interpretation. Pathogenic/likely pathogenic (P/LP) germline variations were found in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, with 6.39% (25/391) of patients carrying P/LP variants in clinically actionable genes (tier 1). About 41.5% of the 53 patients with P/LP variations had mutations in genes involved in the DNA damage response. CHEK2 (8 patients) and DDX41 (8 patients) were the most common mutant genes (7 patients). Pathogenic germline mutations in novel candidate genes were also discovered (DNAH5, DNAH9, DNMT3A, and SUZ12). 

There was no significant association between the rate of germline mutation and the age of AML onset. Around 6 patients with known P/LP germline variants were found among 49 patients with a reported history of at least 1 family member affected with hematological malignancies, and the remaining patients had at least one variant of uncertain significance, indicating the need for additional functional validation studies. Using CHEK2, investigators demonstrated that three-dimensional protein modeling may be an efficient strategy for prioritizing variations of uncertain relevance for functional research.

In addition, they tested an in silico strategy that uses ACMG curation in an automated way in exome studies using the tool for assessment and (TAPES) prioritizing, which could reduce human curation time for variants. Overall, the findings implied that more research was needed to fully understand the predisposition potential of numerous germline variations in order to enable better disease management and therapeutic approaches for affected patients and families.