👪

Inheritance

1

Autosomal dominant HP:0000006

One germline loss-of-function allele is sufficient for the increased risk, and offspring of a carrier have a 50% chance of inheriting it. Penetrance is low: with a population lifetime uveal melanoma risk of about 7.7 per 100,000, the 2021 relative risk of about 9 corresponds to a lifetime risk below 0.1%, which is consistent with the absence of familial or bilateral uveal melanoma among the first eight carriers. A familial case was later reported among 25 carrier families. Larger relative-risk estimates (31.44 in a 2026 update of the same French cohort) would raise this figure, and a Finnish series found no loss-of-function carrier at all, so no penetrance figure is recorded.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (6 references)

PMID:32239153 SUPPORT Human Clinical

"In summary, we described here a novel autosomal-dominant syndrome that is caused by germline mutations of MBD4, characterized by a high RR of developing hypermutated UM and possibly other malignancies."

The discovery cohort's statement of dominant inheritance.

PMID:32239153 SUPPORT Human Clinical

"With a lifetime risk of UM estimated at 7.69 × 10–5 in the general population (25), an RR of 9 would result in a lifetime risk of UM of 6.92 × 10–4."

The authors' own conversion of relative risk to an absolute lifetime risk, the basis for calling penetrance low.

PMID:32239153 SUPPORT Human Clinical

"none of these individuals had familial or bilateral UM."

No familial aggregation among the first carriers identified.

+ 3 more references

?

Discussions and Knowledge Gaps

4

What is the absolute, age-specific uveal melanoma risk in heterozygous MBD4 carriers, and does it justify ophthalmologic surveillance, and from what age?

KNOWLEDGE GAP OPEN mbd4_um_penetrance_and_surveillance

Attached to

phenotypes#Uveal Melanoma genetic#MBD4

Relative-risk estimates span 9.15 to 31.44 within one French institution, another series found no loss-of-function carrier, and ClinGen held the classification at Moderate for that reason. No heterozygote surveillance protocol was found in the sources cited here; the annual dilated eye examination GeneReviews recommends is for biallelic MBD4-TPDS. All published carrier cases found are adults, so there is no basis for childhood surveillance.

Show evidence (2 references)

PMID:42594245 SUPPORT Human Clinical

"annual dilated eye exam beginning in adulthood"

The only eye-surveillance recommendation found, written for the recessive syndrome.

CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z SUPPORT Other

"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)."

ClinGen's summary of the conflicting case-control evidence.

Do heterozygous MBD4 carriers have an increased risk of tumors other than uveal melanoma?

KNOWLEDGE GAP OPEN mbd4_um_tumor_spectrum

Attached to

genetic#MBD4

Germline heterozygous MBD4 variants have been found in single cases of glioblastoma, spiradenocarcinoma, colorectal, gastric and pancreatic tumors, and carrier families report breast, renal and colorectal cancers in relatives, but no case-control estimate exists for any of them in the sources cited here, and the breast cancer probands came from a series referred for suspected breast cancer predisposition. No phenotype other than uveal melanoma is recorded on this entry for that reason.

Show evidence (2 references)

PMID:32239153 SUPPORT Human Clinical

"Importantly, germline MBD4 mutations were recently reported in other types of malignancy, including a polyposis-associated colorectal adenocarcinoma (20), a spiradenocarcinoma (19), a glioblastoma (8), a pilocytic astrocytoma, a gastric adenocarcinoma, a pancreatic adenocarcinoma, and a..."

Single-case reports of other tumors in carriers.

PMID:38060262 SUPPORT Human Clinical

"Monoallelic MBD4 pathogenic variant may explain some cases of familial and multiple uveal melanoma as well as various cancer types, expanding the tumor spectrum of this predisposition."

The carrier-series authors frame the wider spectrum as possible, not shown.

How does tumor-restricted MBD4 deficiency promote uveal melanoma, and why is the uvea the dominant tumor site in heterozygotes?

KNOWLEDGE GAP OPEN mbd4_um_transformation_mechanism

Attached to

pathophysiology#CpG>TpG Hypermutator Phenotype in Uveal Melanoma

The discovery authors could not say whether MBD4 loss acts by increasing driver mutations, by altering the methylation landscape, or otherwise, and they called the uveal proneness unexplained, offering only that monosomy 3 co-inactivates BAP1 and MBD4. Their working model puts a Gq-pathway activating mutation first, which would explain adult onset but has not been tested in carriers.

Show evidence (2 references)

PMID:32239153 SUPPORT Human Clinical

"Whether MBD4 deficiency favors malignant transformation by increasing driver mutations by modifying the methylation landscape or a distinct mechanism has yet to be determined."

The authors state the mechanism is unresolved.

PMID:32239153 SUPPORT Human Clinical

"remains unexplained, but the fact that the frequent M3 in UM inactivates wild-type copies of both BAP1 and MBD4 suppressor genes may at least in part explain the frequent inactivation of MBD4 in UM."

The tissue-specificity question and the authors' partial explanation.

Are MBD4-deficient uveal melanomas selectively sensitive to cytidine analogs such as gemcitabine in patients?

KNOWLEDGE GAP OPEN mbd4_um_cytidine_analog_sensitivity

Attached to

pathophysiology#Unrepaired G:T Mismatches at Methyl-CpG in Tumor Cells

A drug-repurposing screen in isogenic MBD4-knockout cells, one uveal melanoma patient-derived xenograft and one patient's tumor response point to synthetic lethality with cytidine analogs. That is a single clinical observation, so no cytidine-analog treatment is curated on this entry.

Show evidence (2 references)

PMID:36323843 SUPPORT In Vitro

"After a large-scale drug repurposing screen, we show in two isogenic MBD4 knock-out cell models that the inactivation of MBD4 sensitizes cancer cells to cytidine analogs."

The cell-model synthetic-lethality result.

PMID:36323843 SUPPORT Human Clinical

"treatment in the corresponding patient resulted in an exceptional tumor response"

The single patient response.

⚙

Pathophysiology

4

Heterozygous Germline MBD4 Loss of Function

One constitutional MBD4 allele carries a truncating, canonical-splice or catalytically dead missense variant. Every cell keeps one functional allele, so the constitutional state is not itself a mutator state; it is a first hit awaiting loss of the wild-type allele in a uveal melanocyte. Recurrent alleles across unrelated carriers (c.1562-1G>T, c.1443delT, c.1706G>A, c.335+1G>A, c.939dup) suggest founder effects.

Genetic context MBD4 hgnc:6919 variant_origin: GERMLINE allelic_hit_role: FIRST_HIT functional_impact_category: LOSS_OF_FUNCTION

Heterozygous germline loss-of-function variants, including frameshift, nonsense, canonical splice and glycosylase-dead missense (p.Arg468Trp) alleles.

G/T mismatch-specific thymine-DNA glycosylase activity GO:0141016 ↓ DECREASED

Downstream

Somatic Loss of the Wild-Type MBD4 Allele by Chromosome 3 Loss

Show evidence (4 references)

PMID:32239153 SUPPORT Human Clinical

"Taken together, we thus identified 8 LoF germline variants in MBD4 among the 1093 consecutive UM case patients, including p. Arg468Trp with deleterious effect on MBD4 glycosylase activity (Table 1)."

The allele classes seen in carriers, including a missense allele shown to abolish glycosylase activity.

PMID:32239153 SUPPORT In Vitro

"The assay confirmed that p. Trp569* results in a catalytically inactive protein and further demonstrated p. Arg468Trp to be a LoF variant (Figure 1)."

In vitro glycosylase assay of carrier alleles; graded IN_VITRO because the quoted sentence reports the recombinant-protein assay.

CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z SUPPORT Other

"The mechanism of pathogenicity appears to be loss-of-function."

ClinGen's assessment of the disease mechanism for the dominant uveal melanoma relationship.

+ 1 more reference

Somatic Loss of the Wild-Type MBD4 Allele by Chromosome 3 Loss

In every sequenced tumor from a carrier, the wild-type MBD4 allele (3q21.3) was lost by monosomy 3 or isodisomy 3. Because BAP1 (3p21) lies on the same chromosome, the same event removes the wild-type BAP1 allele, and the carrier tumors with available profiles also carried somatic BAP1 inactivation. MBD4 deficiency in uveal melanoma is therefore tied to monosomy-3, high-metastatic-risk tumors.

uveal melanocyte CL:0000148

Genetic context MBD4 hgnc:6919 variant_origin: SOMATIC allelic_hit_role: SECOND_HIT functional_impact_category: LOSS_OF_FUNCTION

Loss of heterozygosity of the wild-type MBD4 allele by monosomy 3 or isodisomy 3 in the tumor.

G/T mismatch-specific thymine-DNA glycosylase activity GO:0141016 ↓ DECREASED

uvea UBERON:0001768

Downstream

Unrepaired G:T Mismatches at Methyl-CpG in Tumor Cells

Show evidence (4 references)

PMID:32239153 SUPPORT Human Clinical

"We confirmed that the 3 MBD4 germline LoF mutations were associated with somatic loss of the wild-type allele in the tumors by either M3 (UM75 and UM605) or isodisomy 3 (UM656)"

Tumor-level loss of the wild-type allele in carrier tumors from the consecutive series.

PMID:32239153 SUPPORT Human Clinical

"Out of these 5 UM case patients with germline MBD4 variants, 4 had available tumor profiles that all showed M3 and somatic BAP1 inactivation (8,9,16), presumably because of the localization of both MBD4 and BAP1 on chromosome 3."

Co-inactivation of BAP1 by the same chromosome 3 loss in carrier tumors.

PMID:29760383 SUPPORT Human Clinical

"We identified a germline deleterious frameshift deletion of MBD4 (3q21.3; c.1441delT:p.F481Dfs*9) with loss of the second allele by monosomy 3 in all tumor samples (Fig. 2c, f)."

Index case in which every tumor sample lost the second allele through monosomy 3.

+ 1 more reference

Unrepaired G:T Mismatches at Methyl-CpG in Tumor Cells

With both alleles gone, the tumor cell can no longer excise thymine from the G:T mispair produced by spontaneous deamination of 5-methylcytosine, so the mispair persists into replication. The defect is confined to the tumor lineage, not present constitutionally as in biallelic MBD4-TPDS.

uveal melanoma cell CL:0000148

base-excision repair initiated by removal of deaminated bases GO:0097510 ↓ DECREASED

Downstream

CpG>TpG Hypermutator Phenotype in Uveal Melanoma

Show evidence (3 references)

PMID:32239153 SUPPORT Human Clinical

"MBD4 encodes a glycosylase involved in the base excision repair of DNA damage arising from spontaneous deamination of 5-methylcytosine to thymine"

Names the repair step lost when the second allele is gone.

PMID:10499592 SUPPORT In Vitro

"Furthermore, the methyl-CpG binding domain of MBD4 binds preferentially to m5CpG x TpG mismatches-the primary product of deamination at methyl-CpG."

Identifies the deaminated methyl-CpG mispair as MBD4's preferred substrate.

PMID:37957685 SUPPORT In Vitro

"Here we show that the protein MBD4 is required for DNA methylation maintenance and G/T mismatch repair."

Experimental confirmation that MBD4 loss abolishes G/T mismatch repair.

CpG>TpG Hypermutator Phenotype in Uveal Melanoma

Carrier tumors carry a median of about 243 exome variants against 16 in MBD4-proficient uveal melanoma, with 85-96% of single-nucleotide variants being CpG>TpG transitions against about a quarter in other uveal melanomas. The excess continues after dissemination: metastases from MBD4-deficient tumors are genetically heterogeneous and acquire new drivers (TP53, SMARCA4, GNAS), whereas MBD4-proficient metastases acquire few new variants. How the mutator contributes to malignant transformation, beyond accompanying it, has not been determined (see discussions).

Animal models

Mbd4 knockout mouse Mouse partially recapitulates Reproduces the CpG-specific transition excess that follows loss of both MBD4 alleles.

Downstream

Uveal Melanoma The predisposition is to hypermutated monosomy-3 uveal melanoma. Which step of transformation the mutator accelerates is not known; the discovery authors propose that it acts only after a Gq-pathway initiating mutation.

Show evidence (4 references)

PMID:32239153 SUPPORT Human Clinical

"Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype."

The mutator phenotype in every carrier tumor sequenced.

PMID:32239153 SUPPORT Human Clinical

"Taken together, these 7 patients with MBD4 deleterious mutations had a 15-fold increase in number of variants per exome"

Quantifies the mutator effect relative to MBD4-proficient uveal melanoma.

PMID:29760383 SUPPORT Human Clinical

"Over 91% of mutations were CpG>TpG transitions, compared to <30% in other UMs (Fig. 2b)."

CpG specificity of the excess mutations in the index carrier's tumors.

+ 1 more reference

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

1

Uveal Melanoma Neoplastic HP:0007716

Onset: ADULT

Show evidence (6 references)

PMID:32239153 SUPPORT Human Clinical

"We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population"

Case-control enrichment of germline MBD4 loss-of-function among 1093 consecutive uveal melanoma patients.

PMID:42060275 SUPPORT Human Clinical

"A total of 23 of 896 patients were identified as carrying an MBD4 germline pathogenic or likely pathogenic variant, corresponding to a relative risk of 31.44 (95% CI, 18.18-53.00) of developing uveal melanoma compared with the general population"

Larger, later relative-risk estimate from the same institution with non-Finnish European gnomAD as reference.

PMID:30714079 SUPPORT Human Clinical

"Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was > 20 times higher than in an aggregated population genome database (P < 5 × 10-5), implying a potential role as UM predisposition gene."

Independent pooled estimate of enrichment across published uveal melanoma cohorts.

+ 3 more references

🧬

Genetic Associations

1

MBD4 (Heterozygous germline loss-of-function variants in MBD4 increase the risk of hypermutated monosomy-3 uveal melanoma.)

Gene: MBD4 hgnc:6919 gene page relationship_type: RISK_FACTOR variant_origin: GERMLINE

Show evidence (4 references)

CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z SUPPORT Other

ClinGen gene-disease validity row (Moderate, autosomal dominant), recorded against the tumor MONDO term.

CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z SUPPORT Other

"This classification was kept at moderate due to a study with conflicting case-control data (PMID: 32421892)."

ClinGen's reason for not raising the tier.

CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z SUPPORT Other

"Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability."

The ClinGen lump/split decision this entry follows.

+ 1 more reference

💊

Medical Actions

2

Immune Checkpoint Blockade for Metastatic MBD4-Deficient Uveal Melanoma

Action: immune checkpoint inhibitor therapy Ontology label: Immunotherapy NCIT:C15262

Agent: pembrolizumab NCIT:C106432 nivolumab NCIT:C68814 ipilimumab NCIT:C2654

Platform: Monoclonal antibody

Anti-PD-1 monotherapy or anti-PD-1 with anti-CTLA-4 for metastatic disease. In unselected metastatic uveal melanoma, response rates are below 5%; in MBD4-deficient tumors, a retrospective series of 12 patients (most of them germline carriers, some with somatic MBD4 loss only) reported a 50% response rate, and in a 300-patient retrospective cohort 3 of 5 MBD4-mutated patients responded against 4% of wild-type. The evidence is retrospective and rests on small numbers, and how checkpoint blockade should be sequenced with tebentafusp in HLA-A*02:01-positive carriers is unresolved.

Mechanism Target:

CpG>TpG Hypermutator Phenotype in Uveal Melanoma

Show evidence (7 references)

PMID:42788773 SUPPORT Human Clinical

"The overall response rate was 50% (two complete, four partial) with a disease control rate of 83%."

Response in 12 MBD4-mutated metastatic patients treated with checkpoint inhibitors.

PMID:42788773 SUPPORT Human Clinical

"We identified 25 patients carrying germline MDB4 mutations (n = 25/29, 86.2%) and five with somatic alterations of MBD4 (13.8%), among whom 18 presented with metastases (62%)."

Most patients in the source population were germline carriers (the "MDB4" typo is the source's).

PMID:42788773 SUPPORT Human Clinical

"Unlike cutaneous melanoma, metastatic uveal melanoma (mUM) generally responds poorly to immunotherapy, with reported response rates of <5% in unselected populations."

Baseline response rate in unselected metastatic uveal melanoma, for comparison.

+ 4 more references

Genetic Counseling and Cascade Testing of Relatives

Action: Genetic Counseling NCIT:C15240

Dominant counselling: first-degree relatives of a carrier have a 50% chance of carrying the variant. Because absolute risk is low and no heterozygote-specific surveillance protocol was found in the sources cited here, counselling centres on testing relatives and on informing tumor management if uveal melanoma develops. Relatives of a biallelic MBD4-TPDS proband who carry one familial variant are counselled about the same uveal melanoma risk.

Show evidence (2 references)

PMID:42594245 SUPPORT Human Clinical

"Once the MBD4 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."

GeneReviews statement that heterozygote testing of relatives is available once the familial variant is known.

PMID:38060262 SUPPORT Human Clinical

"Further genetic testing in relatives combined with molecular tumor analyses will help define the tumor spectrum and estimate each tumor's risk."

Carrier-series authors recommend testing relatives.

🔬

Diagnosis

1

Germline MBD4 testing in uveal melanoma

The predisposition is identified by germline MBD4 testing of a person with uveal melanoma, or by cascade testing of relatives once a familial variant is known. A hypermutated, CpG>TpG-dominant, monosomy-3 tumor is a clue to MBD4 deficiency, but somatic MBD4 inactivation also occurs, so germline status needs a constitutional sample. Practice differs between guidelines: NCCN lists MBD4 among the uveal melanoma testing genes and ASCO recommends BAP1 alone (per a secondary report; the guideline texts were not read for this entry). MBD4 was absent from older multigene panels, so an earlier negative panel does not exclude a carrier state.

Genetic Testing NCIT:C15709

Show evidence (4 references)

PMID:42415513 SUPPORT Human Clinical

"Currently, the NCCN UM genetic testing guidelines list five genes: BAP1, BRCA1, BRCA2, PALB2, and MBD4, to be associated with genetic predisposition to UM, while the ASCO guidelines recommend testing for only a single gene, BAP1"

Secondary report of the NCCN and ASCO testing recommendations.

PMID:42415513 SUPPORT Human Clinical

"In addition, MBD4 and other recently implicated UM predisposition genes were not included on earlier versions of the testing panels."

Supports the caution about earlier negative panels.

PMID:42060275 SUPPORT Human Clinical

"This reinforces a strategy of broad patient screening given the therapeutic implications and the consequences of genetic counseling."

Authors' recommendation of broad germline screening of uveal melanoma patients.

+ 1 more reference

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from MBD4-Related Uveal Melanoma Predisposition:

BAP1 tumor predisposition syndrome

Overlapping Features The other established germline uveal melanoma predisposition, and the one with higher penetrance.

Distinguishing Features

Uveal melanoma penetrance is much higher in BAP1 carriers than in MBD4 heterozygotes.
A CpG>TpG hypermutated tumor points to MBD4 deficiency.
In neither predisposition is uveal melanoma onset shifted earlier than in non-carriers.

Show evidence (1 reference)

PMID:32239153 SUPPORT Human Clinical

"Interestingly, the same is observed in germline BAP1-mutant carriers, even with the high penetrance in that context (6,23)."

Contrasts BAP1's high penetrance with MBD4 while noting the shared absence of early onset.

🐁

Animal Models

1

Mbd4 knockout mouse

Constitutional Mbd4-null mice. They model the tumor-cell state of a carrier's uveal melanoma (both alleles lost), not the heterozygous germline state, and no uveal or melanocytic phenotype is reported.

Species

Mouse

Genotype

Mbd4-/- (homozygous null)

Publication

PMID:12130785

Pathograph links

CpG>TpG Hypermutator Phenotype in Uveal Melanoma partially recapitulates fidelity: low observes: molecular Reproduces the CpG-specific transition excess that follows loss of both MBD4 alleles.

Limitations: Measured in normal mouse tissues, not in melanocytes or uveal melanoma, and at a two- to three-fold increase rather than the roughly 15-fold exome-wide excess in human carrier tumors. Heterozygous mice show no increased cancer susceptibility, and the model does not address uveal melanoma.

Show evidence (2 references)

PMID:12130785 SUPPORT Model Organism

"We tested this hypothesis by analyzing Mbd4-/- mice and found that the frequency of of C --> T transitions at CpG sites was increased by a factor of three."

Threefold increase in CpG transitions on loss of both alleles (the doubled "of" is the source's).

+ 1 more reference

{ }

Source YAML

click to show

name: MBD4-Related Uveal Melanoma Predisposition
creation_date: "2026-10-15T14:19:12Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
parents:
- susceptibility to uveal melanoma
disease_term:
  preferred_term: melanoma, uveal, susceptibility to, 1
  term:
    id: MONDO:0011695
    label: melanoma, uveal, susceptibility to, 1
synonyms:
- UVM1
- melanoma, uveal, susceptibility to, type 1
- MBD4-related uveal melanoma susceptibility
- autosomal dominant MBD4 uveal melanoma predisposition
description: >-
  Autosomal dominant, low-penetrance susceptibility to uveal melanoma conferred by
  a heterozygous germline loss-of-function variant in MBD4, the methyl-CpG-binding
  glycosylase that removes thymine from the G:T mispair left when
  5-methylcytosine deaminates. Unlike the recessive MBD4-related tumor
  predisposition syndrome, a heterozygote's normal cells keep one working allele;
  the tumor follows a Knudson two-hit route in which the second hit is loss of
  chromosome 3 (monosomy 3 or isodisomy 3), which removes the wild-type MBD4
  allele and, from the same chromosome, the wild-type BAP1 allele. Only then is
  the melanocyte MBD4-deficient, and the resulting uveal melanomas are monosomy-3,
  high-risk tumors carrying a CpG>TpG hypermutator phenotype, about 15-fold more
  exome variants than MBD4-proficient uveal melanoma in a cancer that otherwise
  has one of the lowest mutation burdens. Metastatic MBD4-deficient uveal
  melanoma responds to immune checkpoint blockade far more often than unselected
  metastatic uveal melanoma. Relative-risk estimates from consecutive Institut
  Curie series are 9.15 and 31.44, but a Finnish series of 440 patients found no
  loss-of-function carrier, and the absolute lifetime risk implied by the first
  estimate is under 0.1%, so most carriers never develop the tumor. Onset in
  carriers is in adulthood and was not earlier than in non-carriers in the first
  series (median 55.5 years); no uveal melanoma in a child or adolescent
  heterozygote was found in the sources cited here. Whether heterozygotes carry an
  excess risk of other cancers is not established.
notes: >-
  Lump/split. ClinGen split MBD4-related disease into autosomal dominant uveal
  melanoma susceptibility (OMIM 606660) and autosomal recessive tumor
  predisposition syndrome 2 (OMIM 619975), on differences in inheritance pattern
  and phenotypic variability. This entry is the dominant half; the recessive half
  is MBD4-Related_Tumor_Predisposition_Syndrome. Heterozygous relatives of an
  MBD4-TPDS proband are heterozygotes in the sense of this entry. Anchor. The
  disease term is the germline susceptibility concept MONDO:0011695, not
  MONDO:0006486 uveal melanoma, which is the tumor term that the somatic
  Uveal_Melanoma entry anchors to (design decisions section 3a). ClinGen recorded
  its autosomal dominant assertion against MONDO:0006486, so that Moderate
  assertion is cited as evidence below but is not recorded in
  gene_disease_validity, which requires the assertion's MONDO term to be this
  entry's disease term. Somatic Gq-pathway and BAP1/SF3B1/EIF1AX biology of
  uveal melanoma is curated in Uveal_Melanoma and is repeated here only where the
  MBD4-deficient tumor differs from it.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    One germline loss-of-function allele is sufficient for the increased risk,
    and offspring of a carrier have a 50% chance of inheriting it. Penetrance is
    low: with a population lifetime uveal melanoma risk of about 7.7 per 100,000,
    the 2021 relative risk of about 9 corresponds to a lifetime risk below 0.1%,
    which is consistent with the absence of familial or bilateral uveal melanoma
    among the first eight carriers. A familial case was later reported among 25
    carrier families. Larger relative-risk estimates (31.44 in a 2026 update of
    the same French cohort) would raise this figure, and a Finnish series found
    no loss-of-function carrier at all, so no penetrance figure is recorded.
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, we described here a novel autosomal-dominant syndrome that is caused by germline mutations of MBD4, characterized by a high RR of developing hypermutated UM and possibly other malignancies."
    explanation: The discovery cohort's statement of dominant inheritance.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With a lifetime risk of UM estimated at 7.69 × 10–5 in the general population (25), an RR of 9 would result in a lifetime risk of UM of 6.92 × 10–4."
    explanation: The authors' own conversion of relative risk to an absolute lifetime risk, the basis for calling penetrance low.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "none of these individuals had familial or bilateral UM."
    explanation: No familial aggregation among the first carriers identified.
  - reference: PMID:38060262
    reference_title: "Familial uveal melanoma and other tumors in 25 families with monoallelic germline MBD4 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Family histories showed the first familial case of uveal melanoma in monoallelic MBD4 pathogenic variant carriers and other various types of cancers in relatives, especially breast, renal, and colorectal tumors."
    explanation: First familial uveal melanoma in heterozygous carriers.
  - reference: CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MBD4 | HGNC:6919 | uveal melanoma | MONDO:0006486 | AD | Moderate"
    explanation: ClinGen records the uveal melanoma relationship with autosomal dominant inheritance.
  - reference: PMID:42594245
    reference_title: "MBD4-Related Tumor Predisposition Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous family members of an individual with MBD4-TPDS have a relative risk of 9.15-31.44 to develop uveal melanoma compared to the general population."
    explanation: >-
      GeneReviews applies the heterozygote uveal melanoma risk to relatives of a
      recessive MBD4-TPDS proband, who fall under this entry.
pathophysiology:
- name: Heterozygous Germline MBD4 Loss of Function
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    One constitutional MBD4 allele carries a truncating, canonical-splice or
    catalytically dead missense variant. Every cell keeps one functional allele,
    so the constitutional state is not itself a mutator state; it is a first hit
    awaiting loss of the wild-type allele in a uveal melanocyte. Recurrent alleles
    across unrelated carriers (c.1562-1G>T, c.1443delT, c.1706G>A, c.335+1G>A,
    c.939dup) suggest founder effects.
  genetic_context:
    gene:
      preferred_term: MBD4
      term:
        id: hgnc:6919
        label: MBD4
    variant_origin: GERMLINE
    allelic_hit_role: FIRST_HIT
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous germline loss-of-function variants, including frameshift,
      nonsense, canonical splice and glycosylase-dead missense (p.Arg468Trp)
      alleles.
  molecular_functions:
  - preferred_term: G/T mismatch-specific thymine-DNA glycosylase activity
    term:
      id: GO:0141016
      label: G/T mismatch-specific thymine-DNA glycosylase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, we thus identified 8 LoF germline variants in MBD4 among the 1093 consecutive UM case patients, including p. Arg468Trp with deleterious effect on MBD4 glycosylase activity (Table 1)."
    explanation: The allele classes seen in carriers, including a missense allele shown to abolish glycosylase activity.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The assay confirmed that p. Trp569* results in a catalytically inactive protein and further demonstrated p. Arg468Trp to be a LoF variant (Figure 1)."
    explanation: In vitro glycosylase assay of carrier alleles; graded IN_VITRO because the quoted sentence reports the recombinant-protein assay.
  - reference: CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity appears to be loss-of-function."
    explanation: ClinGen's assessment of the disease mechanism for the dominant uveal melanoma relationship.
  - reference: PMID:10499592
    reference_title: "The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that MBD4, an unrelated mammalian protein that contains a methyl-CpG binding domain, can also efficiently remove thymine or uracil from a mismatches CpG site in vitro."
    explanation: >-
      Biochemical definition of the glycosylase activity reduced by the germline
      variant (the "mismatches" typo is the source's own).
  downstream:
  - target: Somatic Loss of the Wild-Type MBD4 Allele by Chromosome 3 Loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32239153
      reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MBD4, located on chromosome 3, is thought to act as a tumor suppressor gene, following Knudson’s 2-hit model with loss of the wild-type allele by monosomy 3 (M3) in UMs (8)."
      explanation: States the two-hit model linking the germline allele to tumor-level loss of the wild-type allele.
- name: Somatic Loss of the Wild-Type MBD4 Allele by Chromosome 3 Loss
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  role: effector
  biological_scale: MOLECULAR
  description: >-
    In every sequenced tumor from a carrier, the wild-type MBD4 allele (3q21.3)
    was lost by monosomy 3 or isodisomy 3. Because BAP1 (3p21) lies on the same
    chromosome, the same event removes the wild-type BAP1 allele, and the
    carrier tumors with available profiles also carried somatic BAP1
    inactivation. MBD4 deficiency in uveal melanoma is therefore tied to
    monosomy-3, high-metastatic-risk tumors.
  genetic_context:
    gene:
      preferred_term: MBD4
      term:
        id: hgnc:6919
        label: MBD4
    variant_origin: SOMATIC
    allelic_hit_role: SECOND_HIT
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Loss of heterozygosity of the wild-type MBD4 allele by monosomy 3 or
      isodisomy 3 in the tumor.
  molecular_functions:
  - preferred_term: G/T mismatch-specific thymine-DNA glycosylase activity
    term:
      id: GO:0141016
      label: G/T mismatch-specific thymine-DNA glycosylase activity
    modifier: DECREASED
  cell_types:
  - preferred_term: uveal melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  locations:
  - preferred_term: uvea
    term:
      id: UBERON:0001768
      label: uvea
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We confirmed that the 3 MBD4 germline LoF mutations were associated with somatic loss of the wild-type allele in the tumors by either M3 (UM75 and UM605) or isodisomy 3 (UM656)"
    explanation: Tumor-level loss of the wild-type allele in carrier tumors from the consecutive series.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Out of these 5 UM case patients with germline MBD4 variants, 4 had available tumor profiles that all showed M3 and somatic BAP1 inactivation (8,9,16), presumably because of the localization of both MBD4 and BAP1 on chromosome 3."
    explanation: Co-inactivation of BAP1 by the same chromosome 3 loss in carrier tumors.
  - reference: PMID:29760383
    reference_title: "Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a germline deleterious frameshift deletion of MBD4 (3q21.3; c.1441delT:p.F481Dfs*9) with loss of the second allele by monosomy 3 in all tumor samples (Fig. 2c, f)."
    explanation: Index case in which every tumor sample lost the second allele through monosomy 3.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding confirms that MBD4 deficiency in UM is mainly associated with M3 and that MBD4 germline mutations specifically predispose to hypermutated high-risk M3 UMs."
    explanation: Restriction of MBD4-deficient uveal melanoma to the monosomy 3 subgroup.
  downstream:
  - target: Unrepaired G:T Mismatches at Methyl-CpG in Tumor Cells
    causal_link_type: DIRECT
- name: Unrepaired G:T Mismatches at Methyl-CpG in Tumor Cells
  conforms_to: "genome_instability_mutation#Failure of DNA Damage Surveillance and Repair"
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    With both alleles gone, the tumor cell can no longer excise thymine from the
    G:T mispair produced by spontaneous deamination of 5-methylcytosine, so the
    mispair persists into replication. The defect is confined to the tumor
    lineage, not present constitutionally as in biallelic MBD4-TPDS.
  biological_processes:
  - preferred_term: base-excision repair initiated by removal of deaminated bases
    term:
      id: GO:0097510
      label: base-excision repair, AP site formation via deaminated base removal
    modifier: DECREASED
  cell_types:
  - preferred_term: uveal melanoma cell
    term:
      id: CL:0000148
      label: melanocyte
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MBD4 encodes a glycosylase involved in the base excision repair of DNA damage arising from spontaneous deamination of 5-methylcytosine to thymine"
    explanation: Names the repair step lost when the second allele is gone.
  - reference: PMID:10499592
    reference_title: "The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, the methyl-CpG binding domain of MBD4 binds preferentially to m5CpG x TpG mismatches-the primary product of deamination at methyl-CpG."
    explanation: Identifies the deaminated methyl-CpG mispair as MBD4's preferred substrate.
  - reference: PMID:37957685
    reference_title: "MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that the protein MBD4 is required for DNA methylation maintenance and G/T mismatch repair."
    explanation: Experimental confirmation that MBD4 loss abolishes G/T mismatch repair.
  downstream:
  - target: CpG>TpG Hypermutator Phenotype in Uveal Melanoma
    causal_link_type: DIRECT
- name: CpG>TpG Hypermutator Phenotype in Uveal Melanoma
  conforms_to: "genome_instability_mutation#Mutator Phenotype and Chromosomal Instability"
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Carrier tumors carry a median of about 243 exome variants against 16 in
    MBD4-proficient uveal melanoma, with 85-96% of single-nucleotide variants
    being CpG>TpG transitions against about a quarter in other uveal melanomas.
    The excess continues after dissemination: metastases from MBD4-deficient
    tumors are genetically heterogeneous and acquire new drivers (TP53, SMARCA4,
    GNAS), whereas MBD4-proficient metastases acquire few new variants. How the
    mutator contributes to malignant transformation, beyond accompanying it, has
    not been determined (see discussions).
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype."
    explanation: The mutator phenotype in every carrier tumor sequenced.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, these 7 patients with MBD4 deleterious mutations had a 15-fold increase in number of variants per exome"
    explanation: Quantifies the mutator effect relative to MBD4-proficient uveal melanoma.
  - reference: PMID:29760383
    reference_title: "Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 91% of mutations were CpG>TpG transitions, compared to <30% in other UMs (Fig. 2b)."
    explanation: CpG specificity of the excess mutations in the index carrier's tumors.
  - reference: PMID:31227496
    reference_title: "Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations."
    explanation: Continued mutagenesis and new driver acquisition during metastatic progression.
  downstream:
  - target: Uveal Melanoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The predisposition is to hypermutated monosomy-3 uveal melanoma. Which step
      of transformation the mutator accelerates is not known; the discovery
      authors propose that it acts only after a Gq-pathway initiating mutation.
    evidence:
    - reference: PMID:32239153
      reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We further demonstrated that MBD4 deficiency specifically predisposes to high-risk M3 UM."
      explanation: Links MBD4 deficiency to the monosomy 3 uveal melanoma outcome.
phenotypes:
- category: Neoplastic
  name: Uveal Melanoma
  description: >-
    The defining tumor. Primary uveal melanoma in carriers has been unilateral
    and single in nearly all reported cases, with one carrier with multiple
    uveal melanomas among 25 French carrier families. Carrier tumors are
    monosomy-3, hypermutated, and in the first series had metastasis-free and
    overall survival not different from MBD4-proficient monosomy-3 tumors.
    Median age at diagnosis was 55.5 years in the first eight carriers, not
    earlier than in non-carriers, and the discovery authors' model places the
    rate-limiting first step (a Gq-pathway activating mutation) upstream of any
    MBD4 effect, which they offer as the reason onset is not shifted earlier. No
    pediatric case was found in the sources cited here.
  phenotype_term:
    preferred_term: Uveal melanoma
    term:
      id: HP:0007716
      label: Uveal melanoma
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population"
    explanation: Case-control enrichment of germline MBD4 loss-of-function among 1093 consecutive uveal melanoma patients.
  - reference: PMID:42060275
    reference_title: "Prevalence of the Predisposing Gene MBD4 for Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 23 of 896 patients were identified as carrying an MBD4 germline pathogenic or likely pathogenic variant, corresponding to a relative risk of 31.44 (95% CI, 18.18-53.00) of developing uveal melanoma compared with the general population"
    explanation: Larger, later relative-risk estimate from the same institution with non-Finnish European gnomAD as reference.
  - reference: PMID:30714079
    reference_title: "Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was > 20 times higher than in an aggregated population genome database (P < 5 × 10-5), implying a potential role as UM predisposition gene."
    explanation: Independent pooled estimate of enrichment across published uveal melanoma cohorts.
  - reference: PMID:32421892
    reference_title: "Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified no LOF variants though their frequency in the Finnish population is 0.052%. Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM."
    explanation: >-
      The conflicting case-control study; 440 Finnish patients without a single
      loss-of-function carrier. ClinGen kept the classification at Moderate
      because of it.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One surprising observation for this new cancer-predisposing condition is the absence of early-onset UM."
    explanation: Basis for adult onset and for not shifting the onset category earlier.
  - reference: PMID:38060262
    reference_title: "Familial uveal melanoma and other tumors in 25 families with monoallelic germline MBD4 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighteen of these families presented with uveal melanoma (including a case patient with multiple uveal melanoma), and 7 families presented with breast cancer."
    explanation: Uveal melanoma, including one multiple-primary case, in a second carrier series.
genetic:
- name: MBD4
  gene_term:
    preferred_term: MBD4
    term:
      id: hgnc:6919
      label: MBD4
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  association: >-
    Heterozygous germline loss-of-function variants in MBD4 increase the risk of
    hypermutated monosomy-3 uveal melanoma.
  notes: >-
    relationship_type is RISK_FACTOR rather than CAUSATIVE. The schema reserves
    CAUSATIVE for ClinGen Definitive or Strong, and ClinGen rates this pair
    Moderate (autosomal dominant, Hereditary Cancer GCEP, 2026-02-27), kept there
    because of conflicting case-control data. The variant is also neither
    sufficient (estimated lifetime risk below 0.1%) nor necessary (under 3% of
    consecutive uveal melanoma patients carry one), which is the RISK_FACTOR
    definition. That ClinGen assertion is recorded against MONDO:0006486 uveal
    melanoma rather than this entry's MONDO:0011695, so it is cited in evidence
    and not copied into gene_disease_validity.
  case_fractions:
  - population: Consecutive uveal melanoma patients, Institut Curie, France, 2013-2018
    case_fraction_percent: 0.7
    cohort_size: 1093
    notes: Germline loss-of-function variants including one glycosylase-dead missense allele; approximate figure as stated by the authors.
    evidence:
    - reference: PMID:32239153
      reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we demonstrate that the prevalence of MBD4 germline deleterious variants in UM is approximately 0.7%, close to that of BAP1 germline mutation in UM (1.6%) (23), and that MBD4 mutations strongly predispose to UM with an RR of 9.15 (95% CI = 4.24 to 19.73)."
      explanation: Share of consecutive uveal melanoma cases carrying a germline MBD4 loss-of-function variant.
  - population: Uveal melanoma patients, Institut Curie, France, February 2021 to September 2025
    cohort_size: 896
    notes: 23 of 896 patients carried a pathogenic or likely pathogenic variant; the abstract gives the count, not a percentage, so none is recorded here. 319 patients overlap with earlier evaluations.
    evidence:
    - reference: PMID:42060275
      reference_title: "Prevalence of the Predisposing Gene MBD4 for Uveal Melanoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a case series involving 896 individuals, including 319 who were previously evaluated, germline target-sequencing of MBD4 was offered to every new patient with uveal melanoma at Curie Institute from February 2021 to September 2025."
      explanation: Cohort definition for the 23 of 896 count quoted under the uveal melanoma phenotype.
  - population: Finnish uveal melanoma patients
    case_fraction_percent: 0.23
    case_fraction_low: 0.01
    case_fraction_high: 1.28
    cohort_size: 432
    notes: One likely pathogenic missense variant; no loss-of-function variant was found.
    evidence:
    - reference: PMID:32421892
      reference_title: "Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The frequency of likely pathogenic variants in our cohort is 0.23% (1/432; 95% CI, 0.01-1.28)."
      explanation: Case fraction in a population-based Finnish series.
  evidence:
  - reference: CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MBD4 | HGNC:6919 | uveal melanoma | MONDO:0006486 | AD | Moderate"
    explanation: ClinGen gene-disease validity row (Moderate, autosomal dominant), recorded against the tumor MONDO term.
  - reference: CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This classification was kept at moderate due to a study with conflicting case-control data (PMID: 32421892)."
    explanation: ClinGen's reason for not raising the tier.
  - reference: CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability."
    explanation: The ClinGen lump/split decision this entry follows.
  - reference: PMID:35460607
    reference_title: "Germline MBD4 deficiency causes a multi-tumor predisposition syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to findings with uveal melanoma where heterozygotes for MBD4 LOF variants appear to be at a 4- to 20-fold increased risk, our limited data show no convincing evidence for a comparable effect on the relative risk of developing polyposis and/or CRC."
    explanation: >-
      The recessive-syndrome authors' summary of the heterozygote uveal melanoma
      risk, and their finding that polyposis and colorectal cancer risk is not
      shown in heterozygotes.
diagnosis:
- name: Germline MBD4 testing in uveal melanoma
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    The predisposition is identified by germline MBD4 testing of a person with
    uveal melanoma, or by cascade testing of relatives once a familial variant is
    known. A hypermutated, CpG>TpG-dominant, monosomy-3 tumor is a clue to
    MBD4 deficiency, but somatic MBD4 inactivation also occurs, so germline
    status needs a constitutional sample. Practice differs between guidelines:
    NCCN lists MBD4 among the uveal melanoma testing genes and ASCO recommends
    BAP1 alone (per a secondary report; the guideline texts were not read for
    this entry). MBD4 was absent from older multigene panels, so an earlier
    negative panel does not exclude a carrier state.
  evidence:
  - reference: PMID:42415513
    reference_title: "Impact of Multigene Panel Testing in High-Risk Uveal Melanoma Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, the NCCN UM genetic testing guidelines list five genes: BAP1, BRCA1, BRCA2, PALB2, and MBD4, to be associated with genetic predisposition to UM, while the ASCO guidelines recommend testing for only a single gene, BAP1"
    explanation: Secondary report of the NCCN and ASCO testing recommendations.
  - reference: PMID:42415513
    reference_title: "Impact of Multigene Panel Testing in High-Risk Uveal Melanoma Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, MBD4 and other recently implicated UM predisposition genes were not included on earlier versions of the testing panels."
    explanation: Supports the caution about earlier negative panels.
  - reference: PMID:42060275
    reference_title: "Prevalence of the Predisposing Gene MBD4 for Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This reinforces a strategy of broad patient screening given the therapeutic implications and the consequences of genetic counseling."
    explanation: Authors' recommendation of broad germline screening of uveal melanoma patients.
  - reference: PMID:42788773
    reference_title: "Survival of Patients With MBD4-Mutated Metastatic Uveal Melanoma Treated With Immune Checkpoint Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beyond clinical implications, our findings argue for systematic testing of MBD4 status in uveal melanoma, ideally through both somatic and germline analyses."
    explanation: Supports testing both tumor and constitutional DNA.
treatments:
- name: Immune Checkpoint Blockade for Metastatic MBD4-Deficient Uveal Melanoma
  description: >-
    Anti-PD-1 monotherapy or anti-PD-1 with anti-CTLA-4 for metastatic disease.
    In unselected metastatic uveal melanoma, response rates are below 5%; in
    MBD4-deficient tumors, a retrospective series of 12 patients (most of them
    germline carriers, some with somatic MBD4 loss only) reported a 50% response
    rate, and in a 300-patient retrospective cohort 3 of 5 MBD4-mutated patients
    responded against 4% of wild-type. The evidence is retrospective and rests on
    small numbers, and how checkpoint blockade should be sequenced with
    tebentafusp in HLA-A*02:01-positive carriers is unresolved.
  treatment_term:
    preferred_term: immune checkpoint inhibitor therapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
    - preferred_term: nivolumab
      term:
        id: NCIT:C68814
        label: Nivolumab
    - preferred_term: ipilimumab
      term:
        id: NCIT:C2654
        label: Ipilimumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  target_mechanisms:
  - target: CpG>TpG Hypermutator Phenotype in Uveal Melanoma
  evidence:
  - reference: PMID:42788773
    reference_title: "Survival of Patients With MBD4-Mutated Metastatic Uveal Melanoma Treated With Immune Checkpoint Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall response rate was 50% (two complete, four partial) with a disease control rate of 83%."
    explanation: Response in 12 MBD4-mutated metastatic patients treated with checkpoint inhibitors.
  - reference: PMID:42788773
    reference_title: "Survival of Patients With MBD4-Mutated Metastatic Uveal Melanoma Treated With Immune Checkpoint Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 25 patients carrying germline MDB4 mutations (n = 25/29, 86.2%) and five with somatic alterations of MBD4 (13.8%), among whom 18 presented with metastases (62%)."
    explanation: Most patients in the source population were germline carriers (the "MDB4" typo is the source's).
  - reference: PMID:42788773
    reference_title: "Survival of Patients With MBD4-Mutated Metastatic Uveal Melanoma Treated With Immune Checkpoint Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike cutaneous melanoma, metastatic uveal melanoma (mUM) generally responds poorly to immunotherapy, with reported response rates of <5% in unselected populations."
    explanation: Baseline response rate in unselected metastatic uveal melanoma, for comparison.
  - reference: PMID:35863105
    reference_title: "MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded"
    explanation: Comparative response rate in a 300-patient metastatic cohort; germline and somatic MBD4 mutations are not separated in the quoted result.
  - reference: PMID:29760383
    reference_title: "Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor."
    explanation: The index germline carrier whose response led to the discovery.
  - reference: PMID:30714079
    reference_title: "Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient experienced stable disease (10 months) and survived 2 years with metastatic disease, which is twice as long as median survival."
    explanation: An independent germline carrier with prolonged disease control on combination checkpoint blockade.
  - reference: PMID:42788773
    reference_title: "Survival of Patients With MBD4-Mutated Metastatic Uveal Melanoma Treated With Immune Checkpoint Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Another major question is the choice of the first systemic line in HLA-A02:01–positive, MBD4-mutated cases, as tebentafusp is currently the recommended standard."
    explanation: The unresolved sequencing question with tebentafusp.
- name: Genetic Counseling and Cascade Testing of Relatives
  description: >-
    Dominant counselling: first-degree relatives of a carrier have a 50% chance
    of carrying the variant. Because absolute risk is low and no
    heterozygote-specific surveillance protocol was found in the sources cited
    here, counselling centres on testing relatives and on informing tumor
    management if uveal melanoma develops. Relatives of a biallelic MBD4-TPDS
    proband who carry one familial variant are counselled about the same uveal
    melanoma risk.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42594245
    reference_title: "MBD4-Related Tumor Predisposition Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the MBD4 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
    explanation: GeneReviews statement that heterozygote testing of relatives is available once the familial variant is known.
  - reference: PMID:38060262
    reference_title: "Familial uveal melanoma and other tumors in 25 families with monoallelic germline MBD4 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further genetic testing in relatives combined with molecular tumor analyses will help define the tumor spectrum and estimate each tumor's risk."
    explanation: Carrier-series authors recommend testing relatives.
differential_diagnoses:
- name: BAP1 tumor predisposition syndrome
  description: >-
    The other established germline uveal melanoma predisposition, and the one
    with higher penetrance.
  distinguishing_features:
  - Uveal melanoma penetrance is much higher in BAP1 carriers than in MBD4 heterozygotes.
  - A CpG>TpG hypermutated tumor points to MBD4 deficiency.
  - In neither predisposition is uveal melanoma onset shifted earlier than in non-carriers.
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, the same is observed in germline BAP1-mutant carriers, even with the high penetrance in that context (6,23)."
    explanation: Contrasts BAP1's high penetrance with MBD4 while noting the shared absence of early onset.
- name: MBD4-Related Tumor Predisposition Syndrome
  description: >-
    The autosomal recessive MBD4 disease caused by biallelic loss of function,
    with a constitutional mutator state.
  disease_term:
    preferred_term: tumor predisposition syndrome 2
    term:
      id: MONDO:0859267
      label: tumor predisposition syndrome 2
  distinguishing_features:
  - Biallelic carriers develop early-onset adenomatous polyposis and AML or MDS, with uveal melanoma as one of several further tumors.
  - Polyposis and colorectal cancer risk has not been shown in heterozygotes.
  evidence:
  - reference: PMID:42594245
    reference_title: "MBD4-Related Tumor Predisposition Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MBD4-related tumor predisposition syndrome (MBD4-TPDS) is characterized by early-onset gastrointestinal polyposis and acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)."
    explanation: GeneReviews definition of the recessive syndrome.
  - reference: PMID:35460607
    reference_title: "Germline MBD4 deficiency causes a multi-tumor predisposition syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to findings with uveal melanoma where heterozygotes for MBD4 LOF variants appear to be at a 4- to 20-fold increased risk, our limited data show no convincing evidence for a comparable effect on the relative risk of developing polyposis and/or CRC."
    explanation: The phenotypic boundary between heterozygotes and biallelic carriers.
animal_models:
- name: Mbd4 knockout mouse
  species: Mouse
  genotype: Mbd4-/- (homozygous null)
  publication: PMID:12130785
  description: >-
    Constitutional Mbd4-null mice. They model the tumor-cell state of a
    carrier's uveal melanoma (both alleles lost), not the heterozygous germline
    state, and no uveal or melanocytic phenotype is reported.
  modeled_mechanisms:
  - target: CpG>TpG Hypermutator Phenotype in Uveal Melanoma
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Reproduces the CpG-specific transition excess that follows loss of both
      MBD4 alleles.
    limitations: >-
      Measured in normal mouse tissues, not in melanocytes or uveal melanoma, and
      at a two- to three-fold increase rather than the roughly 15-fold exome-wide
      excess in human carrier tumors. Heterozygous mice show no increased cancer
      susceptibility, and the model does not address uveal melanoma.
    evidence:
    - reference: PMID:12130785
      reference_title: "Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We tested this hypothesis by analyzing Mbd4-/- mice and found that the frequency of of C --> T transitions at CpG sites was increased by a factor of three."
      explanation: Threefold increase in CpG transitions on loss of both alleles (the doubled "of" is the source's).
    - reference: PMID:12417741
      reference_title: "Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous and homozygous Mbd4 mutant mice develop normally and do not show increased cancer susceptibility or reduced survival."
      explanation: Neither heterozygous nor homozygous mice show spontaneous tumor predisposition.
discussions:
- discussion_id: mbd4_um_penetrance_and_surveillance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the absolute, age-specific uveal melanoma risk in heterozygous MBD4
    carriers, and does it justify ophthalmologic surveillance, and from what age?
  attaches_to:
  - "phenotypes#Uveal Melanoma"
  - "genetic#MBD4"
  rationale: >-
    Relative-risk estimates span 9.15 to 31.44 within one French institution,
    another series found no loss-of-function carrier, and ClinGen held the
    classification at Moderate for that reason. No heterozygote surveillance
    protocol was found in the sources cited here; the annual dilated eye
    examination GeneReviews recommends is for biallelic MBD4-TPDS. All
    published carrier cases found are adults, so there is no basis for
    childhood surveillance.
  evidence:
  - reference: PMID:42594245
    reference_title: "MBD4-Related Tumor Predisposition Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual dilated eye exam beginning in adulthood"
    explanation: The only eye-surveillance recommendation found, written for the recessive syndrome.
  - reference: CGGV:assertion_d97335a9-7e38-4f2c-a59f-f35fd047594a-2026-02-27T180000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "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)."
    explanation: ClinGen's summary of the conflicting case-control evidence.
- discussion_id: mbd4_um_tumor_spectrum
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do heterozygous MBD4 carriers have an increased risk of tumors other than
    uveal melanoma?
  attaches_to:
  - "genetic#MBD4"
  rationale: >-
    Germline heterozygous MBD4 variants have been found in single cases of
    glioblastoma, spiradenocarcinoma, colorectal, gastric and pancreatic tumors,
    and carrier families report breast, renal and colorectal cancers in
    relatives, but no case-control estimate exists for any of them in the
    sources cited here, and the breast cancer probands came from a series
    referred for suspected breast cancer predisposition. No phenotype other than
    uveal melanoma is recorded on this entry for that reason.
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, germline MBD4 mutations were recently reported in other types of malignancy, including a polyposis-associated colorectal adenocarcinoma (20), a spiradenocarcinoma (19), a glioblastoma (8), a pilocytic astrocytoma, a gastric adenocarcinoma, a pancreatic adenocarcinoma, and a pancreatic endocrine tumor (21)"
    explanation: Single-case reports of other tumors in carriers.
  - reference: PMID:38060262
    reference_title: "Familial uveal melanoma and other tumors in 25 families with monoallelic germline MBD4 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monoallelic MBD4 pathogenic variant may explain some cases of familial and multiple uveal melanoma as well as various cancer types, expanding the tumor spectrum of this predisposition."
    explanation: The carrier-series authors frame the wider spectrum as possible, not shown.
- discussion_id: mbd4_um_transformation_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does tumor-restricted MBD4 deficiency promote uveal melanoma, and why is
    the uvea the dominant tumor site in heterozygotes?
  attaches_to:
  - "pathophysiology#CpG>TpG Hypermutator Phenotype in Uveal Melanoma"
  rationale: >-
    The discovery authors could not say whether MBD4 loss acts by increasing
    driver mutations, by altering the methylation landscape, or otherwise, and
    they called the uveal proneness unexplained, offering only that monosomy 3
    co-inactivates BAP1 and MBD4. Their working model puts a Gq-pathway
    activating mutation first, which would explain adult onset but has not been
    tested in carriers.
  evidence:
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whether MBD4 deficiency favors malignant transformation by increasing driver mutations by modifying the methylation landscape or a distinct mechanism has yet to be determined."
    explanation: The authors state the mechanism is unresolved.
  - reference: PMID:32239153
    reference_title: "Germline MBD4 Mutations and Predisposition to Uveal Melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "remains unexplained, but the fact that the frequent M3 in UM inactivates wild-type copies of both BAP1 and MBD4 suppressor genes may at least in part explain the frequent inactivation of MBD4 in UM."
    explanation: The tissue-specificity question and the authors' partial explanation.
- discussion_id: mbd4_um_cytidine_analog_sensitivity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Are MBD4-deficient uveal melanomas selectively sensitive to cytidine analogs
    such as gemcitabine in patients?
  attaches_to:
  - "pathophysiology#Unrepaired G:T Mismatches at Methyl-CpG in Tumor Cells"
  rationale: >-
    A drug-repurposing screen in isogenic MBD4-knockout cells, one uveal
    melanoma patient-derived xenograft and one patient's tumor response point to
    synthetic lethality with cytidine analogs. That is a single clinical
    observation, so no cytidine-analog treatment is curated on this entry.
  evidence:
  - reference: PMID:36323843
    reference_title: "Cytidine analogs are synthetic lethal with base excision repair default due to MBD4 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "After a large-scale drug repurposing screen, we show in two isogenic MBD4 knock-out cell models that the inactivation of MBD4 sensitizes cancer cells to cytidine analogs."
    explanation: The cell-model synthetic-lethality result.
  - reference: PMID:36323843
    reference_title: "Cytidine analogs are synthetic lethal with base excision repair default due to MBD4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment in the corresponding patient resulted in an exceptional tumor response"
    explanation: The single patient response.
references:
- reference: PMID:42594245
  title: "MBD4-Related Tumor Predisposition Syndrome."
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:42594245

MBD4-Related Tumor Predisposition Syndrome.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: MBD4-Related_Uveal_Melanoma_Predisposition · 2026-10-15T14:48:19Z · View source

New entry for the autosomal dominant uveal melanoma susceptibility conferred by heterozygous germline MBD4 loss of function (MONDO:0011695, OMIM 606660), following the ClinGen split from the recessive MBD4-TPDS (MBD4-Related_Tumor_Predisposition_Syndrome, not edited). Anchored on the susceptibility term rather than MONDO:0006486 (tumor term, somatic Uveal_Melanoma entry). The ClinGen AD Moderate assertion (CGGV:assertion_d97335a9..., cached from the 2026-10-14 ClinGen export via clingen-rebuild --csv) is recorded against MONDO:0006486, so it is cited as evidence and not recorded in gene_disease_validity; check-gene-validity reports it as other_disease. relationship_type RISK_FACTOR (ClinGen Moderate; variant neither necessary nor sufficient). Pathograph: germline first hit -> chromosome 3 loss second hit (co-inactivating BAP1) -> tumor-restricted G:T mismatch repair loss -> CpG>TpG hypermutator -> uveal melanoma. Sources: Derrien 2021 (full text), Rodrigues 2018 (full text), Villy 2024, Repo 2020 (REFUTE), Johansson 2019, JAMA Ophthalmol 2026, Saint-Ghislain 2022, Curie ICI series 2026, Ohio panel study 2026, ClinGen record, GeneReviews MBD4-TPDS chapter, mouse knockouts. Deep research: falcon failed authentication (503) twice and --fallback did not engage, so one claude_code report was run and used only as a lead; it read search snippets only, and its ellipsis-joined Palles quote (flagged unsupported by the validator) and NCI PDQ and Portuguese-series claims were not used. preflight-dr exited 2 (no local mondo.db). Gaps: no penetrance figure, no heterozygote surveillance protocol found, tumor spectrum beyond uveal melanoma unestablished, no pediatric cases in cited sources, NCCN/ASCO guideline texts not read (cited via a secondary report). Validated with just validate, count-verified-snippets (62/62), validate-terms, entity-ref, causal-target, duplicate-key, qualifier, genereviews, gene-term-mismatch and block-scalar checks, and validate-disorders.

Claude Code ▸

MBD4-Related Uveal Melanoma Predisposition: Research Report

claude-haiku-5-5, claude-sonnet-5-5 8 citations 2026-10-15T14:23:14.995748

MBD4-Related Uveal Melanoma Predisposition: Research Report

Source and verification status. This report comes from three standard web searches. I read search-result summaries and snippets, not full papers. I did not open the full Derrien, Palles, Sanders or Rodrigues papers, and the supplied sources do not cover several template sections (flagged "Not retrieved"). Items marked [unverified, from background knowledge] are lead-class model recall, not sourced. They must not go into YAML without a primary-source check. I give PMC or URL identifiers rather than PMIDs where I did not see the PMID in a result. Every CURIE below is a suggestion that needs an OAK or cache lookup before binding.

Lump/split flag. The entry name "MBD4-Related Uveal Melanoma Predisposition" conflates two genetic states, and the sources diverge sharply on them. - Biallelic germline MBD4 loss is an autosomal recessive multi-tumor syndrome, MBD4-associated neoplasia syndrome (MANS). It is established in the sources I saw (Palles et al. 2022, PMC9118112; NCI PDQ). - Monoallelic germline MBD4 loss plus somatic loss of the second allele in the tumor is the uveal melanoma (UM) predisposition described by Derrien et al. The risk estimates are large but contested. A Finnish series found germline loss-of-function (LoF) variants rare in UM, and the NCI PDQ summary, as relayed by the Haematologica review, calls the heterozygous-risk data conflicting.

I could not tell from the search results which of these MONDO:0011695 actually represents. Check this before curation. If the term is the UM-predisposition concept, a possible split is a MANS entry (recessive, multi-tumor) plus a UM-predisposition entry or has_subtypes row. Keep germline syndromes separate from the somatic tumors they predispose to (design-decisions §3a).

1. Disease Information

Overview. MBD4 encodes a DNA glycosylase in base excision repair (BER). It removes thymine from G:T mismatches created by deamination of 5-methylcytosine. Loss produces a CpG>TpG (C>T) hypermutator phenotype. Tumors in carriers are hypermutated with a CpG>TpG excess. Source classes: primary literature (Derrien 2021, Rodrigues 2018) and the NCI PDQ summary, via search snippets.
Identifiers. MONDO:0011695 comes from the template and I did not verify it. OMIM, Orphanet, ICD and MeSH identifiers: Not retrieved.
Synonyms. "MBD4-associated neoplasia syndrome (MANS)" appears in the NCI PDQ title. "Germline MBD4 deficiency / multi-tumor predisposition syndrome" appears in the JCI Insight reference-list title.
Individual or aggregated data. The evidence is individual-level: case reports, family series and consecutive UM cohorts. No aggregated disease-level resource was reviewed.

2. Etiology

Causal factor. Germline LoF variants in MBD4.
Biallelic: "autosomal recessive, multi-organ tumor predisposition syndrome… five individuals with bi-allelic MBD4 variants within four families, with histories of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma" (Palles et al. 2022, PMC9118112, via search snippet).
Monoallelic: Derrien et al. (JNCI 2021, PMC7781447 per search listing) report "8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% CI = 4.24–19.73) increased incidence compared with the general population." Tumors carrying them "were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype."
A larger Curie series, per the Institut Curie listing: 23/896 UM patients carried a germline P/LP MBD4 variant, relative risk 31.44. I only saw the snippet.
Contrary evidence. Repo et al. 2020 reported germline LoF MBD4 variants rare in Finnish UM patients (via Haematologica snippet). A 2024 study found UM and other tumors in 25 families with monoallelic variants (PMID:38060262, title only). Its findings were not retrieved.
Environmental and protective factors, gene-environment interactions. Not retrieved. UV is not established in UM etiology, and I did not source this.
Modifier genes. Not retrieved.

3. Phenotypes

Source for the table: Palles et al. 2022 (biallelic); Derrien 2021 (monoallelic). Frequencies, onset and quality-of-life data were not retrieved, so no percentages are given.

Phenotype	Candidate HP term	Context
Uveal melanoma	HP:0007716 (uveal melanoma) [unverified]	Both monoallelic and biallelic
Colorectal adenomatous polyposis	HP:0005227 [unverified]	Biallelic
Acute myeloid leukemia	HP:0004808 [unverified]	Biallelic and Sanders 2018 (see below)
Clonal hematopoiesis / MDS	HP:0002863 (MDS) [unverified]	Haematologica review snippet
Schwannomatosis	not verified	NCI PDQ testing criteria mention it

Pediatric framing. The sources I saw do not give onset ages. Whether MANS has pediatric onset is not established here. The question needs the case-level ages in Palles 2022 and Sanders 2018.

4. Genetic/Molecular

Gene. MBD4 (HGNC symbol; use the lowercase hgnc: form, ID not looked up).
Variants. LoF (nonsense, frameshift, splice and similar), but the specific variants and ACMG classes were not retrieved. Population allele frequencies (gnomAD) were not retrieved.
Somatic second hit. Heterozygous germline variants with somatic loss of the wild-type allele are reported in UM (Haematologica snippet). Rodrigues et al. 2018 (PMC5951831) describe a "germline deleterious mutation, and somatic MBD4 inactivation in the tumor" in an exceptional anti-PD-1 responder.
Signature. SBS1 (clock-like CpG>TpG), seen in the colorectal adenomas of MBD4-deficient individuals (Palles 2022).
ClinGen validity. Not retrieved. Do not infer a tier.
Epigenetics and chromosomal abnormalities. Not retrieved.

6. Mechanism: causal chain

Germline LoF in one or both MBD4 alleles. In the monoallelic case, somatic loss of the second allele in the tumor (reported, PMC5951831) creates biallelic deficiency in that tissue.
MBD4 no longer removes thymine from G:T mismatches arising from deamination of 5-methylcytosine (function per Palles 2022 snippet).
Unrepaired mismatches are replicated, which leads to CpG>TpG substitutions and the SBS1-dominant mutator phenotype (Palles 2022; Derrien 2021).
The accumulating mutations probably include driver hits (inferred; the specific UM drivers were not retrieved), which leads to tumor formation in tissues at risk: uveal melanocytes, colonic epithelium, hematopoietic cells.
In UM, the result is a hypermutated tumor, unusual for a typically low-TMB cancer (Derrien 2021).
Hypermutation likely increases neoantigen load, which leads to checkpoint-inhibitor sensitivity. This is inferred and is supported only by case and cohort data (see §12).
Why UM specifically is unexplained in the sources I saw. Treat that as a gap.
Suggested GO terms [unverified]: base-excision repair (GO:0006284), DNA N-glycosylase activity (GO:0019104). Cell types: melanocyte (CL:0000148), hematopoietic stem cell (CL:0000037), colonic epithelial cell. Verify all by lookup.
Omics, single-cell, spatial and functional screens. Not retrieved.

7. Anatomical structures

Uvea and eye: uveal tract (UBERON:0001768 [unverified]). Laterality was not retrieved.
Colon (adenomas) and bone marrow (AML, clonal hematopoiesis).
Subcellular: nucleus.
Metastatic site: metastatic UM is treated in the cohort below. The metastatic sites (the liver is typical for UM) were not sourced in my results.

8. Temporal development

Onset, progression, remission. Not retrieved.
Critical periods. Not retrieved. MANS onset in childhood versus adulthood is the key open question for the pediatric framing.

9. Inheritance and population

Biallelic: autosomal recessive (Palles 2022).
Monoallelic UM predisposition: autosomal dominant-like with tumor-level second hit, but penetrance is undefined.
Case counts. The NCI PDQ summary cites nine reported cases, and a later Portuguese series reports 11 individuals from eight families (search-result snippets; I did not open the primary papers).
Prevalence and incidence, founder effects, carrier frequency, sex ratio. Not retrieved. Derrien's 9.15-fold and the Curie RR of 31.44 are relative figures, not penetrance. They need the denominators in the papers.

10. Diagnostics

Testing. NCI PDQ suggests germline testing for "AML patients with high mutational burden enriched for CG>GT variants, or with a history of colonic polyposis, schwannomatosis, or uveal melanoma" (snippet, paraphrased by the search tool).
Tumor sequencing. A CpG>TpG-dominant, high-TMB profile in a UM should prompt MBD4 testing (inferred from Derrien 2021 and Rodrigues 2018).
Everything else. GTR panels, GeneReviews and guidelines: Not retrieved. Differential diagnosis and screening protocols: Not retrieved.

11. Prognosis

Not retrieved for the predisposition syndrome. The only outcome data I have are for metastatic UM treated with checkpoint inhibitors (see §12).

12. Treatment

Checkpoint inhibitors.
Rodrigues et al. 2018 (PMC5951831): a single metastatic UM patient with "exceptional high sensitivity to a PD-1 inhibitor" and an outlier CpG>TpG mutation burden.
Saint-Ghislain et al. 2022 (Eur J Cancer), per a search summary: 300 metastatic UM patients on checkpoint inhibitors; 5 of the 131 sequenced tumors (3.8%) carried MBD4 mutations; 3 of 5 MBD4-mutant patients responded versus about 4% of wild-type; the summary gave median PFS of 4.0 months (wild-type) versus 22.3 months (mutant). The numbers rest on five patients, and I did not verify them in the full paper. The authors propose MBD4 as a tissue-agnostic biomarker.
Whether TMB alone explains the response is unresolved.
Suggested NCIT terms [unverified]: immunotherapy (NCIT:C15262), Pharmacotherapy (NCIT:C15986, from the repo guidance). Candidate therapeutic_agent entries are anti-PD-1 agents such as pembrolizumab and nivolumab (look up the CHEBI or NCIT agent term). No specific drug or regimen was named in my search results, so I should not assert one.
Surveillance (colonoscopy, ophthalmologic exam, hematologic monitoring): Not retrieved, and I will not infer guidelines.
Clinical trials, pharmacogenomics, advanced therapeutics: Not retrieved.

13. Prevention

Not retrieved. Genetic counseling and cascade testing follow from the recessive and dominant-like inheritance, but I have no sourced guideline.

14–15. Other species and model organisms

Not retrieved. I know of Mbd4 knockout mice in the literature [unverified, from background knowledge], but I did not search for them or their phenotypes.

Gaps to close before curation

Confirm the scope of MONDO:0011695 (see the lump/split flag).
Pull Derrien 2021 (PMC7781447), Palles 2022 (PMC9118112) and Rodrigues 2018 (PMC5951831) in full, to get exact snippets, PMIDs, variant lists and ages.
Get Sanders 2018 (Blood, MBD4 and clonal hematopoiesis/AML) and Saint-Ghislain 2022. I know them only from search-result summaries.
Get ClinGen validity, GeneReviews and Orphanet, and a surveillance guideline, if any exists.
Resolve the contested heterozygous risk by reading Repo 2020 and PMID:38060262 against Derrien.

Sources (search-result level)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	0
Quoted claims not found in source	1
References weighed for topical relevance	4
On topic	4
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMC:PMC9118112: "autosomal recessive, multi-organ tumor predisposition syndrome… five individuals with bi-allelic MBD4 variants within four families, with histories of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma"
closest text in source: "We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	12
Resolved	12
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	2
Terms named correctly	1
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0002863 (1 mention) - the report calls it "MDS"; HP calls it Myelodysplasia

MBD4-Related Uveal Melanoma Predisposition

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

MBD4-Related Uveal Melanoma Predisposition: Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular

6. Mechanism: causal chain

7. Anatomical structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Prognosis

12. Treatment

13. Prevention

14–15. Other species and model organisms

Gaps to close before curation

Sources (search-result level)

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else