MBD4

Inheritance Pattern: AR

Disease ID:MONDO:0859267

Submitter: ClinGen

MBD4 was first reported in relation to autosomal MBD4-related recessive tumor predisposition syndrome in 2018 (Saunders et al., PMID: 30049810). This condition is a cancer predisposition syndrome with features such as acute myeloid leukemia, myelodysplastic syndrome, colorectal polyposis and carcinoma, and uveal melanoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal recessive tumor predisposition syndrome (OMIM: 619975) and autosomal dominant uveal melanoma (OMIM: 606660). This curation only focuses on the recessive tumor predisposition syndrome assertion. Susceptibility to uveal melanoma has been curated separately. Six variants (missense, in-frame deletion, nonsense, and frameshift) that have been reported in at least 9 probands in 4 publications (PMIDs: 30049810, 35381620, 35460607; https://doi.org/10.1182/blood-2021-154221) are included in this curation. This gene encodes a protein that recognizes methylated CpG sites and has mismatch-specific glycosylase activity that functions in DNA repair. Deleterious variants lead to C>T mutations at CpG sites, which may be enriched in tumors. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence including a mouse model, functional alteration, and interaction evidence (PMIDs: 17285135, 27086921, 37957685). In the mouse model, homozygous null mice had more serious complications, reduced survival, and a higher tumor burden than wild-type controls. Also, functional alteration evidence showed that MBD4 is necessary for DNA methylation stability and G/T mismatch repair, and enzymatic activity is impaired in mutants. Furthermore, the gene was shown to interact with the MLH1 and PMS2 genes, both of which are definitive for autosomal recessive mismatch repair cancer syndrome and autosomal dominant Lynch Syndrome. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date 7/9/2024 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0006486

Submitter: ClinGen

MBD4 (Methyl-CpG Binding Domain 4) was first reported in relation to autosomal dominant uveal melanoma in 2020 (Repo et al., PMID: 32421892). MBD4 is located on chromosome 3q21.3 and has an MBD region at the N-terminus that attaches to methylated DNA and plays a part in protein interactions. It also has a C-terminal mismatch-specific glycosylase region that plays a role in DNA repair. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, uveal melanoma (OMIM: 606660) and tumor predisposition syndrome 2 (OMIM: 619975). The split curation for autosomal recessive tumor predisposition syndrome 2 has been curated separately. 12 variants (missense, nonsense, frameshift, and splicing) that have been reported in at least 10 probands in 2 publications (PMIDs: 32421892, 38060262) are included in this curation. Additional variants in two case-control studies were included (PMIDs: 32239153, 32421892). One study showed enrichment of loss-of-function variants in affected patients compared to controls (PMID: 32239153), while the other showed no such enrichment of this variant type (PMID: 32421892). Thus, only the former study was scored. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, functional alteration, biochemical function, interaction evidence; PMIDs: 17285135, 27086921, 32239153, 37957685). Experimental evidence shows that the gene plays a role in mismatch repair, tumor prevention, and protection from tissue injury. The MBD4 protein is shown to form a complex with MLH1 and PMS2, both of which are definitively associated with autosomal recessive Mismatch Repair Cancer Syndrome and autosomal dominant Lynch Syndrome. This complex is key in DNA mismatch repair (PMID: 37957685). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively. This classification was kept at moderate due to a study with conflicting case-control data (PMID: 32421892). This classification was approved by the ClinGen Hereditary Cancer GCEP on the meeting date 02/27/2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0859267

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0859267

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0011695

Submitter: Ambry Genetics