GI tract tumours

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: 24 Apr 2025, 8:53 a.m. | Last Modified: 24 Apr 2025, 8:53 a.m.

Panel Version: 1.22

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

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, upgrading from Amber to Green.

Created: 13 Jun 2025, 11:07 a.m. | Last Modified: 13 Jun 2025, 11:07 a.m.

Panel Version: 1.25

- 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