Inherited predisposition to acute myeloid leukaemia (AML)

Gene: MBD4

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Notes from GMS reviewers:
MBD4 is associated with a rare cancer predisposition syndrome with high penetrance for AML. Loss of function of the gene results in defective base excision repair and a mutator phenotype. It is appropriate to include this gene in the panel. Agree with the evidence cited, would seek consensus approval with CGG. As the reports for variants in this gene are limited, it may be prundent to restrict analysis to clearly LOF truncating variants in the first instance. Reagents would require redesign for this gene to be included.

Created: 1 Feb 2023, 8:36 a.m. | Last Modified: 1 Feb 2023, 8:38 a.m.

Panel Version: 2.3

Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing.

MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/) however after GMS consideration it was decided that it should remain amber (v2.23).

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-known cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.

Created: 5 Jul 2022, 3:12 p.m. | Last Modified: 6 Jul 2022, 9:43 a.m.

Panel Version: 1.24

- Palles et al. 2022 (PMID: 35460607) reported on 5 individuals from 4 families with biallelic MBD4 variants who had a personal and/or family history of adenomatous colorectal polyposis (5/5), AML (1/5 personal), and uveal melanoma (2/5 personal). Consistent with previous studies, MBD4-deficient colorectal adenomas showed a significantly increased mutational burden compared to sporadic colorectal tumours, which were mostly attributable to an excess of CpG>TpG transitions.

- Sanders et al. 2018 (PMID: 30049810) demonstrated in 3 individuals with AML (including 2 sibs) and LoF variants in MBD4, that MBD4-deficient cancers exhibit a unique mutational signature with high burden of CpG>TpG transitions. Note that PMID: 32239153 refer to the same individuals.

The MBD4-related hypermutator phenotype has also been detected in Mbd4 mutant mice (PMID:12417741) and other human cancers such as uveal melanoma and colorectal tumours (PMID: 29760383; 32239153; 31322271).

Created: 5 Jul 2022, 1:14 p.m. | Last Modified: 5 Jul 2022, 1:14 p.m.

Panel Version: 1.21

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma

Publications

• 12417741
• 30049810
• 32239153
• 35460607

Green List (high evidence)

Bi-allelic carriers are at a high increased risk of colorectal polyposis, MDS/AML and uveal melanoma. Mono-allelic carriers are not at an increased risk of AML or polyposis in the data we have so far.
Sources: Literature

Created: 30 Jun 2022, 10:53 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
polyposis; CRC; AML; MDS; UVM

Publications

• 35460607