This data relates to a mother-son pair with acute myeloid leukemia, both having a germline mutation P709S in the methyltransferase DNMT3A. Using functional assays in vitro, we demonstrate that the variant P709S has greatly reduced ability to transfer methyl groups to DNA. Germline DNMT3A mutation in a mother-child pair with AML

We report the identification of a germline missense mutation in DNMT3A segregating with the development of diploid acute myeloid leukemia in a mother (I-2) and son (II-1). The P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies of the P709S variant demonstrate the mutation is enzymatically inactive, unable to restore DNA methylation and interacts with and antagonizes wild-type DNMT3A, leading to dominant inhibitory activity. LINE-1 pyrosequencing and reduced representation bisulfite sequencing demonstrated aberrant global and relative DNA hypomethylation in germline samples, not present in the leukemic samples. The acquisition of IDH2 R172K mutations in both patients at the time of AML diagnosis was striking, confirming the important pathogenic interaction of these epigenetically active mutations. While son (II-1) was of tall stature, no convincing evidence of the Tatton-Brown-Rahman overgrowth syndrome related to constitutional DNMT3A mutations was identified.