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→Common Alteration Types
==Common Alteration Types==
==Common Alteration Types==
GATA2 mutations include amino acid substitutions, insertion and deletions, and frameshifts scattered throughout the gene but predominantly found in the region encoding the two zinc finger domains [1]. Approximately 100 GATA2 mutations have been described, either as germline genetic defects or somatic mutations in association with other drivers, such as biallelic CEBPA mutation in AML [1].
• About one-third of all germline mutations are inherited and the rest occur de novo; these include a small number of whole gene deletions and 29 frameshift or nonsense mutations, distributed from the initiation site to the end of the second zinc finger
• A further 11 in-frame insertions or deletions and 54 single nucleotide variants causing amino acid substitution are predominantly found in exons 3, 4 and 5, encoding the two zinc finger domains
• Splice site mutations are also found between coding exons 3 and 4
• Two discrete mutations of the intron 5 enhancer, predicted to affect transcription factor binding, have also been reported
• Overall, approximately two-thirds of all cases described have mutations in the zinc finger domains
• No mutations have been observed in the 5’ or 3’ untranslated regions (UTRs) or in the distal section of the last exon, beyond the region encoding the second zinc finger
• Many single amino acid substitutions are predicted to significantly impair DNA binding of the zinc fingers potentially making them functionally inactive. It is also possible that these variants have residual function or can even act in a dominant negative fashion
• Although more than half the variants described are single amino acid substitutions that may lead to the translation of mutated protein with altered function, it is proposed that the functional effects of heterozygous mutations are primarily due to haploinsufficiency
According to the Catalogue of Somatic Mutations in Cancer (COSMIC), c.490G>A (NM_032638.4) (p.Ala164Thr) and c.15C>G (NM_032638.4) (p.Pro5Pro) have been observed in 49 and 96 cases, respectively, predominantly in the setting of acute myeloid leukemia (https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=GATA2, Accessed 1st August 2018)
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