Inherited polyposis and early onset colorectal cancer - germline testing

Gene: MBD4

Green List (high evidence)

Discussed at Cancer/Scientific Leads/UKCGG council meeting re Test Directory updates 2025/2026 (30/01/2025) - consensus was that evidence is sufficient to warrant addition of this gene to R211 panel as well as R347.

Created: 2 Jun 2025, 9:32 a.m. | Last Modified: 2 Jun 2025, 9:32 a.m.

Panel Version: 3.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
MBD4-Associated Neoplasia Syndrome: Colonic polyposis; colon cancer; uveal melanoma; acute myeloid leukaemia; schwannoma

Publications

• PMID: 35460607
• 30049810
• 35381620
• 32421892
• 32239153

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 10 Dec 2025, 5:36 p.m. | Last Modified: 10 Dec 2025, 5:36 p.m.

Panel Version: 3.10

Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, submitting again as it should be updated to Green at the next GMS panel update.

This gene is also now green on the R347 signed-off panel (v3.0).

Created: 13 Jun 2025, 11:03 a.m. | Last Modified: 13 Jun 2025, 11:03 a.m.

Panel Version: 3.2

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.

Created: 30 Jan 2023, 5:43 p.m. | Last Modified: 30 Jan 2023, 5:43 p.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, 3:15 p.m. | Last Modified: 6 Jul 2022, 9:43 a.m.

Panel Version: 1.32

- 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, 3:13 p.m. | Last Modified: 5 Jul 2022, 3:13 p.m.

Panel Version: 1.19

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 loss of function mutation carriers at high risk of early onset AML, colorectal polyposis an uveal melanoma. Heterozygous monoallelic carriers at no significantly increased risk in data so far.
Sources: Literature

Created: 30 Jun 2022, 10:47 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
polyposis; CRC; AML; MDS; UVM

Publications

• 35460607