Gene affected:
DNMT3A (DNA (cytosine-5)-methyltransferase 3 alpha gene (NM_022552.4))

Clinical significance
There is evidence that mutation affecting DNMT3A may confer adverse outcome in AML and MDS and may influence management plan.
Note DNMT3A is a frequently mutated gene in Age Related Clonal Change (ARCH) and in Clonal Haematopoieisis of Indeterminate Prognosis (CHIP). When etected as part of haematological neoplasia DNMT3A may persist following successful treatment. Interpretation therefore depends significantly on clinical context (see separate section)

Function of gene

DNMT3A is involved in the epigenetic regulation of DNA methylation*; mutation causes loss of DNMT3A function, reducing methylation and allowing the expression of previously silent genes. In haematology, mutations of DNMT3A particularly involve AML and MDS, however the specific downstream target genes affected by DNMT3A mutation in these disorders have not been identified (June 2018).

NGS panel gene coverage

In normal karyotype AML, approximately two-thirds of all DNMT3A mutations affect the arginine residue 882 (R882). These heterozygous R882 mutations affecting one allele cause suppression of the normal allele (dominant-negative effect). Other mutations mechanisms include frameshift/nonsense/splice site changes that do not affect the R882 site. The panel is designed to detect all mutations affecting the essential regions of this gene.


MDS (~8% of MDS)
Associated with poor outcomes in Refractory Anaemia with Excess Blasts (RAEB) and MDS with excess of blasts and MDS with Multi-lineage dysplasia.
AML (~20%)
Linked to a poorer prognosis and shorter overall survival following hematopoietic stem cell transplantation
CHIP (Clonal Haematopoieis of Indeterminate Prognosis) (Up to 50% of cases)
Listed here due to very high frequency in CHIP where it may operate as a driver mutation

Associated genetic features: Often viewed as a potential "driver mutation" in malignancy; the significance of DNMT3A is greatly influenced by the occurrence and nature of any associated genetic changes (this is discussed in the separate section on interpretation of molecular change.


GeneWiki link:
Gene Wiki entry for DNMT3A
1. Adverse prognosis in AML
2. Adverse prognosis in MDS