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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous germline loss-of-function variants confer the predisposition. ClinGen classifies the BARD1 relationship with this MONDO entity as autosomal dominant. No constitutional biallelic BARD1 phenotype is described in the sources used here (see the biallelic knowledge-gap discussion).

Autosomal dominant inheritance

Show evidence (1 reference)

CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z SUPPORT Other

"In summary, there is definitive evidence supporting the relationship between BARD1 and autosomal dominant inherited BARD1-related cancer predisposition."

The ClinGen Hereditary Cancer GCEP curation states the mode of inheritance for this MONDO entity.

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Discussions and Knowledge Gaps

3

Do germline BARD1 loss-of-function variants increase ovarian cancer risk?

CONTROVERSY bard1_ovarian_cancer_disputed

Attached to

disease#

Most case-control data do not support an ovarian association, and ClinGen curated BARD1 and familial ovarian cancer (MONDO:0016248) as a separate gene-disease pair classified Disputed. One study (Norquist 2016) reported BARD1 variants as more common in ovarian carcinoma than in population databases, cautioning that two of its BARD1 carriers also carried BRCA1 variants. Ovarian cancer is therefore not recorded as a phenotype of this entry.

Show evidence (6 references)

CGGV:assertion_02af8326-360e-4f42-a378-fefff7387d97-2024-08-29T170000.000Z REFUTE Other

"In summary, the evidence supporting the relationship between BARD1 and autosomal dominant hereditary ovarian cancer has been disputed and no valid evidence remains to support the claim."

ClinGen's separate ovarian curation disputes the association.

PMID:32679805 REFUTE Human Clinical

"but not an OC risk gene (OR = 1.36, 95% CIs:0.87-2.11, p = 0.1733)"

Pooled analysis of about 20,800 ovarian cancer cases against gnomAD controls found no significant ovarian association.

PMID:26315354 REFUTE Human Clinical

"but no differences for BARD1 (P = .39)"

Case-control sequencing of invasive epithelial ovarian cancer found no difference in BARD1 deleterious-variant frequency between cases and controls.

+ 3 more references

How large is the neuroblastoma risk for a heterozygous BARD1 loss-of-function carrier, and should carriers be surveilled in childhood?

KNOWLEDGE GAP bard1_neuroblastoma_common_vs_rare

Attached to

phenotypes#Neuroblastoma

Two signals must be kept apart. Common BARD1 polymorphisms at 2q35 are associated with high-risk neuroblastoma in GWAS; this is polygenic susceptibility, not this Mendelian entity. Separately, rare germline pathogenic or likely pathogenic BARD1 variants and BARD1-disrupting copy-number variants are enriched in neuroblastoma patients, and ClinGen lumps neuroblastoma into this entity on that case-control evidence. The case-control odds ratios are wide (OR 32.30, 95% CI 6.44 to 310.35 in 786 patients; OR 6.3, 95% CI 2.4 to 13.9 in a pediatric pan-cancer analysis whose cohort overlap with the first study was not assessed here). Absolute childhood penetrance is not reported in these sources, and no source used here gives a neuroblastoma surveillance recommendation for carrier children.

Show evidence (2 references)

PMID:19412175 SUPPORT Human Clinical

"These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma."

The GWAS signal concerns common variants and is outside this Mendelian entity.

PMID:38411636 SUPPORT Other

"The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma."

Review framing of BARD1 as an adult-onset predisposition gene with a pediatric tumor association, which leaves testing and surveillance of children an open question.

Is there a constitutional biallelic BARD1 phenotype in humans?

KNOWLEDGE GAP bard1_biallelic_phenotype_unknown

Attached to

inheritance#Autosomal dominant

Bard1-null mice die between E7.5 and E8.5, and a 2022 review states that BARD1 is not a classic Fanconi anemia gene. A PubMed search, BARD1[ti] AND (biallelic[tiab] OR homozygous[tiab] OR compound heterozygous[tiab]), returned six records, none of which describes a person with constitutional biallelic BARD1 variants. Whether biallelic loss is compatible with human development, and with what phenotype, is unknown.

Show evidence (2 references)

PMID:12832489 SUPPORT Model Organism

"These mice become developmentally retarded and die between embryonic day 7.5 (E7.5) and E8.5."

Constitutional Bard1 nullizygosity is early embryonic lethal in mice.

PMID:35772246 SUPPORT Other

"No data are available regarding reproductive implications. BARD1 is not a classic FA gene."

Review statement that no biallelic Fanconi-like syndrome is established for BARD1.

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Pathophysiology

5

Germline BARD1 Loss of Function

Mechanism confidence: Established

Heterozygous germline nonsense, frameshift, copy-number and selected missense variants reduce functional BARD1. BARD1 is required for the ubiquitin ligase activity of the BRCA1-BARD1 RING heterodimer; individually, BRCA1 and BARD1 have very low ligase activity in vitro. ClinGen describes the pathogenic mechanism as loss of function with disrupted BRCA1 binding and loss of DNA damage response. In isogenic neuroblastoma and RPE1 cells, single-allele truncating variants were sufficient to reduce repair efficiency (haploinsufficiency).

BARD1 hgnc:952

Genetic context BARD1 hgnc:952 variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

BRCA1-BARD1 heterodimer ubiquitin protein ligase activity GO:0061630 ↓ DECREASED

Animal models

Bard1-null mouse Mus musculus perturbs Complete constitutional loss of Bard1.

Downstream

Impaired BRCA1-BARD1 Homologous Recombination Reduced BARD1 dosage lowers BRCA1-BARD1-dependent RAD51 loading and homologous recombination; heterozygous isogenic cells already show the defect.

Show evidence (4 references)

CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z SUPPORT Other

"The mechanism of pathogenicity is loss of function in which BRCA1 binding is disrupted and subsequent loss of DNA damage response."

ClinGen states the disease mechanism for this gene-disease pair.

PMID:11278247 SUPPORT In Vitro

"Whereas individually BRCA1 and BARD1 have very low ubiquitin ligase activities in vitro, BRCA1 combined with BARD1 exhibits dramatically higher activity."

Purified-protein assays show that the ligase activity resides in the heterodimer, so BARD1 loss removes a required partner.

PMID:8944023 SUPPORT In Vitro

"The BARD1/BRCA1 interaction is disrupted by BRCA1 missense mutations that segregate with breast cancer susceptibility, indicating that BARD1 may be involved in mediating tumour suppression by BRCA1."

Original identification of BARD1 as the BRCA1 RING partner, linking the interaction to tumor suppression.

+ 1 more reference

Somatic BARD1 Second-Hit Inactivation

Mechanism confidence: Provisional

Loss of the wild-type BARD1 allele is documented in a subset of carrier tumors but has not been shown to be universal. In a French case-control study, two of seven interpretable carrier breast tumors (both triple-negative primaries) showed loss of heterozygosity with an HRD phenotype, a metastasis showed LOH without HRD, and non-triple-negative primaries had neither. In a child with a germline BARD1 frameshift and refractory neuroblastoma, mono-allelic expression of the variant and loss of BARD1 protein on immunohistochemistry indicated biallelic loss in the tumor.

Genetic context BARD1 hgnc:952 variant_origin: SOMATIC functional_impact_category: LOSS_OF_FUNCTION

Loss of heterozygosity or other inactivation of the remaining allele in a subset of carrier-associated tumors.

Downstream

Impaired BRCA1-BARD1 Homologous Recombination Biallelic loss in the tumor removes residual BRCA1-BARD1 function; in breast tumors it co-occurred with an HRD phenotype.

Show evidence (2 references)

PMID:42496958 SUPPORT Human Clinical

"Among these, two triple-negative (TN) primary tumors exhibited both biallelic BARD1 inactivation via loss of heterozygosity (LOH) and an HRD phenotype; one metastasis displayed LOH without HRD. All non-TN primary tumors lacked both biallelic inactivation and HRD."

Tumor analysis of carrier breast cancers shows the second hit in triple-negative primaries and its absence in non-triple-negative primaries; seven tumors only.

PMID:39141861 SUPPORT Human Clinical

"Immunohistochemical staining of serial BM samples, obtained before talazoparib administration, confirmed somatic BARD1 protein loss"

Single pediatric case documenting tumor-restricted loss of BARD1 protein in a germline heterozygote.

Impaired BRCA1-BARD1 Homologous Recombination

Mechanism confidence: Established

BRCA1-BARD1 binds DNA and RAD51 and stimulates RAD51-mediated synaptic-complex assembly during homologous recombination. BARD1 variants that are non-functional in homology-directed-repair reporter assays sensitize cells to ionizing radiation and cisplatin, and this assay separates known pathogenic from known benign BARD1 variants.

double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED

Downstream

Genomic Instability and Homologous-Recombination Deficiency Failure of error-free double-strand break repair increases DNA damage burden and chromosomal instability.

PARP-Inhibitor and Platinum Sensitivity HR-deficient cells become sensitive to PARP inhibition and cisplatin.

Show evidence (2 references)

PMID:28976962 SUPPORT In Vitro

"we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51."

Purified-protein biochemistry defines a direct BARD1-dependent step in homologous recombination.

PMID:30925164 SUPPORT In Vitro

"Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants."

Cell-based HDR assays align loss of repair function with clinical pathogenicity.

Genomic Instability and Homologous-Recombination Deficiency

Mechanism confidence: Provisional

Common and rare neuroblastoma-associated BARD1 germline variants were associated with lower BARD1 mRNA and higher DNA-damage burden. Bard1-null mouse cells are aneuploid, and mammary-specific Bard1 inactivation produces tumors with high chromosomal instability. HRD has been observed in triple-negative carrier breast tumors with LOH but not in non-triple-negative primaries.

Animal models

Mammary-conditional Bard1 knockout mouse Mus musculus partially recapitulates Reproduces chromosomally unstable triple-negative mammary carcinoma after Bard1 loss.

Downstream

Breast carcinoma Genomic instability in mammary epithelium is the proposed route to the ER-negative and triple-negative breast cancers enriched in carriers.

Neuroblastoma DNA-repair infidelity is proposed by the primary authors as a mechanism contributing to neuroblastoma initiation in carriers.

Show evidence (2 references)

PMID:37688570 SUPPORT Human Clinical

"Both common and rare neuroblastoma-associated BARD1 germline variants were associated with lower levels of BARD1 mRNA and an increased burden of DNA damage."

Genotype-correlation analysis in normal tissues and neuroblastomas links germline BARD1 variation to DNA damage burden.

PMID:12832489 SUPPORT Model Organism

"This result, together with the increased chromosomal aneuploidy of Bard1 mutant cells, indicates a role for Bard1 in maintaining genomic stability."

Complete Bard1 loss in mice causes aneuploidy; this is a null model, not the heterozygous human state.

PARP-Inhibitor and Platinum Sensitivity

Mechanism confidence: Provisional

Heterozygous BARD1 loss-of-function isogenic neuroblastoma cells show increased sensitivity to cisplatin and PARP inhibition in vitro and in vivo. This is a therapeutic vulnerability, not a disease manifestation; clinical evidence is a single pediatric case report.

Show evidence (1 reference)

PMID:37688570 SUPPORT In Vitro

"enhanced sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo"

Isogenic heterozygous models establish the drug sensitivity in cells and in vivo.

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Pathograph

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

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Phenotypes

2

Breast 1

Breast carcinoma HP:0003002

Show evidence (8 references)

CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z SUPPORT Other

"BARD1-related cancer predisposition is characterized by a susceptibility to breast cancer with emerging evidence suggesting the association of other cancer types including neuroblastoma."

ClinGen names breast cancer as the defining manifestation of this entity.

PMID:33471991 SUPPORT Human Clinical

"BARD1 (odds ratio, 2.09; 95% CI, 1.35 to 3.23; P = 0.00098 [P = 0.00011 in all studies])"

BCAC overall breast cancer odds ratio for protein-truncating BARD1 variants in population-based studies.

PMID:33471991 SUPPORT Human Clinical

"For carriers of protein-truncating variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D, the estimated absolute risks by 80 years of age were within the 17 to 30% range for moderate risk"

Absolute-risk estimate placing BARD1 in the moderate-risk category, derived from UK incidences.

+ 5 more references

Context-specific annotations (1)

FEMALE German Consortium for Hereditary Breast and Ovarian Cancer familial index patients, BRCA1/2-negative

Association concentrated in early-onset disease; OR 12.04 below age 40 and not significant at age 50 or older.

Show evidence (2 references)

PMID:31036035 SUPPORT Human Clinical

"In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed."

Age-stratified estimate for the youngest group.

PMID:31036035 SUPPORT Human Clinical

"LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217)."

Age-stratified estimate for the oldest group.

Neoplasm 1

Neuroblastoma HP:0003006

Show evidence (5 references)

PMID:37688579 SUPPORT Human Clinical

"BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35)."

Case-control germline sequencing of 786 neuroblastoma patients against cancer-free controls.

PMID:37688579 SUPPORT Human Clinical

"Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70)."

Copy-number loss-of-function alleles show the same direction of association.

PMID:41066719 SUPPORT Human Clinical

"BARD1 | NBL | 6 in 485 (1.24%) | 31 in 14,477 (0.21%) | 6.3 (2.4 to 13.9)"

Pediatric cancer germline case-control analysis against adult noncancer controls; possible cohort overlap with the 786-patient study was not assessed.

+ 2 more references

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Genetic Associations

1

BARD1

Gene: BARD1 hgnc:952 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z SUPPORT Other

ClinGen Definitive gene-disease validity for BARD1 in this entity.

PMID:32679805 SUPPORT Human Clinical

"The analysis revealed that BARD1 is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25-3.75, p < 0.0001)"

Pooled analysis of about 48,700 breast cancer cases from 123 studies.

PMID:30925164 SUPPORT In Vitro

"From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR."

Functional evidence that missense variants outside the RING domain can abolish repair activity.

+ 1 more reference

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Medical Actions

3

Breast cancer surveillance

Action: breast cancer screening with mammography and breast MRI Ontology label: Cancer Screening NCIT:C15406

A 2022 review table adapted from NCCN v2.2022 lists annual mammography (tomosynthesis) and contrast-enhanced breast MRI starting at age 40, and states that evidence is insufficient for risk-reducing mastectomy, which is managed by family history. The primary GC-HBOC study recommends intensified surveillance on the basis of its early-onset association. Current NCCN text was not checked directly for this entry.

Mechanism Target:

Breast carcinoma — Surveillance detects breast cancer earlier; it does not modify the underlying mechanism.

Show evidence (2 references)

PMID:35772246 SUPPORT Other

"BARD1 | ● Limited emerging evidence to suggest increased risk of female BC (with predisposition to triple negative) ● Unknown or Insufficient evidence for OC or other cancers risk | ● RRM: evidence insufficient, manage based on family history ● Screening: annual mammogram (tomosythesis) and..."

Review table reproducing NCCN v2.2022 management for BARD1, including the absence of an ovarian or other-cancer recommendation.

PMID:31036035 SUPPORT Human Clinical

"Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants."

Primary-study recommendation for surveillance in carriers.

Genetic counseling and cascade testing

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling covers the moderate breast cancer risk, the disputed ovarian association, and the pediatric neuroblastoma association, for which no surveillance recommendation is given in the sources used here. Testing minors for an adult-onset predisposition gene with a pediatric tumor association is an open question.

Show evidence (1 reference)

PMID:38411636 SUPPORT Other

"Examples include heterozygous PVs in BRCA1, RAD51C or BARD1 in childhood neuroblastoma"

Review placing BARD1 among adult-onset predisposition genes found in children with cancer, relevant to pediatric counseling.

Talazoparib in BARD1-associated refractory neuroblastoma

Action: PARP inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: talazoparib CHEBI:231344

Platform: Small molecule

One child with a germline BARD1 frameshift, somatic BARD1 protein loss and refractory high-risk neuroblastoma had a complete bone-marrow response to talazoparib plus irinotecan and remained without clinical evidence of disease 32 months off therapy. This is a single case report plus preclinical data, not an established indication.

Mechanism Target:

PARP-Inhibitor and Platinum Sensitivity — Exploits the homologous-recombination defect of BARD1-deficient tumor cells.

Show evidence (2 references)

PMID:39141861 SUPPORT Human Clinical

"We report the first response of a child with neuroblastoma and a BARD1 germline mutation to a PARPi."

Single pediatric case report of response.

PMID:39141861 SUPPORT Human Clinical

"The patient is 32 months off therapy with no clinical evidence of disease"

Durability in the single reported case.

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Diagnosis

1

Germline molecular diagnosis

Identification of a heterozygous pathogenic or likely pathogenic germline BARD1 variant, usually on a hereditary breast cancer multigene panel; BARD1 variants are also found through paired tumor-normal sequencing of children with neuroblastoma. Missense variants of uncertain significance are common and can be informed by functional HDR assays.

Show evidence (2 references)

PMID:42496958 SUPPORT Human Clinical

"We found a strong enrichment of BARD1 gPV among women selected for personal and family history of breast cancer, reinforcing their relevance for genetic testing for suspected hereditary predisposition."

Supports inclusion of BARD1 in hereditary breast cancer panel testing.

PMID:39141861 SUPPORT Human Clinical

"Paired tumor-normal whole-exome analysis identified a pathogenic germline heterozygous frameshift in BARD1, but no other known driver variants"

Paired tumor-normal sequencing in pediatric oncology is a second ascertainment route.

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Animal Models

2

Mammary-conditional Bard1 knockout mouse

Mammary-specific Bard1 inactivation produced carcinomas indistinguishable from conditional Brca1 and double-mutant tumors in frequency, latency, histopathology and cytogenetics. The tumors were triple-negative and basal-like. The model is biallelic and tissue-restricted, not a heterozygous germline model.

Species

Mus musculus

Genotype

Conditional Bard1 alleles inactivated by Cre in mammary epithelial cells

Publication

PMID:18443292

Pathograph links

Genomic Instability and Homologous-Recombination Deficiency partially recapitulates fidelity: moderate observes: tissue Reproduces chromosomally unstable triple-negative mammary carcinoma after Bard1 loss.

Limitations: Biallelic conditional deletion in mammary epithelium; does not model the heterozygous germline state or the neuroblastoma association.

Show evidence (1 reference)

PMID:18443292 SUPPORT Model Organism

"They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability."

Tumor cytogenetics show chromosomal instability.

Show evidence (1 reference)

PMID:18443292 SUPPORT Model Organism

"Significantly, the conditional Bard1- and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional Bard1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features."

Equivalence of Bard1 and Brca1 tumors supports a heterodimer-mediated tumor-suppressor function.

Bard1-null mouse

Constitutional Bard1 nullizygosity is lethal between E7.5 and E8.5 owing to impaired proliferation, partly ameliorated by p53 loss; mutant cells are aneuploid.

Species

Mus musculus

Genotype

Bard1 homozygous null

Publication

PMID:12832489

Pathograph links

Germline BARD1 Loss of Function perturbs fidelity: low observes: organism Complete constitutional loss of Bard1.

Limitations: Homozygous null and embryonic lethal; informs gene function, not the heterozygous human cancer predisposition.

Show evidence (1 reference)

PMID:12832489 SUPPORT Model Organism

"To explore the genetic relationship between BRCA1 and BARD1, we have examined the phenotype of Bard1-null mice."

The model removes Bard1 entirely.

Show evidence (1 reference)

PMID:12832489 SUPPORT Model Organism

"The striking similarities between the phenotypes of Bard1-null, Brca1-null, and double Bard1; Brca1-null mice provide strong genetic evidence that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer."

Genetic evidence that Bard1 acts through the Brca1/Bard1 heterodimer.

{ }

Source YAML

click to show

name: BARD1-related Cancer Predisposition
creation_date: "2026-10-13T20:15:40Z"
description: >-
  BARD1-related cancer predisposition is an autosomal dominant susceptibility caused by heterozygous germline loss-of-function variants in BARD1, which encodes the obligate RING-domain heterodimeric partner of BRCA1. The BRCA1-BARD1 heterodimer is an E3 ubiquitin ligase and a mediator of RAD51-dependent homologous recombination. Female breast cancer is the established manifestation, at moderate absolute risk, with enrichment for estrogen-receptor-negative and triple-negative tumors and for earlier onset in familial series. Rare germline loss-of-function variants are also enriched in childhood neuroblastoma, which ClinGen lumps into this gene-disease entity. Ovarian cancer is not part of the entity: ClinGen curates BARD1 and familial ovarian cancer separately and classifies that relationship as Disputed. Some carrier-associated tumors show somatic loss of the remaining allele with a homologous-recombination-deficiency phenotype, while heterozygous loss-of-function cell models already show reduced repair efficiency. Common BARD1 polymorphisms associated with high-risk neuroblastoma in GWAS are a separate, non-Mendelian susceptibility signal.
category: Mendelian
synonyms:
- BARD1-associated cancer predisposition
- BARD1 hereditary breast cancer susceptibility
disease_term:
  preferred_term: BARD1-related cancer predisposition
  term:
    id: MONDO:0700267
    label: BARD1-related cancer predisposition
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous germline loss-of-function variants confer the predisposition. ClinGen classifies the BARD1 relationship with this MONDO entity as autosomal dominant. No constitutional biallelic BARD1 phenotype is described in the sources used here (see the biallelic knowledge-gap discussion).
  evidence:
  - reference: CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z
    reference_title: BARD1 / BARD1-related cancer predisposition (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In summary, there is definitive evidence supporting the relationship between BARD1 and autosomal dominant inherited BARD1-related cancer predisposition."
    explanation: The ClinGen Hereditary Cancer GCEP curation states the mode of inheritance for this MONDO entity.
pathophysiology:
- name: Germline BARD1 Loss of Function
  description: >-
    Heterozygous germline nonsense, frameshift, copy-number and selected missense variants reduce functional BARD1. BARD1 is required for the ubiquitin ligase activity of the BRCA1-BARD1 RING heterodimer; individually, BRCA1 and BARD1 have very low ligase activity in vitro. ClinGen describes the pathogenic mechanism as loss of function with disrupted BRCA1 binding and loss of DNA damage response. In isogenic neuroblastoma and RPE1 cells, single-allele truncating variants were sufficient to reduce repair efficiency (haploinsufficiency).
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  evidence:
  - reference: CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z
    reference_title: BARD1 / BARD1-related cancer predisposition (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is loss of function in which BRCA1 binding is disrupted and subsequent loss of DNA damage response."
    explanation: ClinGen states the disease mechanism for this gene-disease pair.
  - reference: PMID:11278247
    reference_title: The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Whereas individually BRCA1 and BARD1 have very low ubiquitin ligase activities in vitro, BRCA1 combined with BARD1 exhibits dramatically higher activity."
    explanation: Purified-protein assays show that the ligase activity resides in the heterodimer, so BARD1 loss removes a required partner.
  - reference: PMID:8944023
    reference_title: Identification of a RING protein that can interact in vivo with the BRCA1 gene product.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The BARD1/BRCA1 interaction is disrupted by BRCA1 missense mutations that segregate with breast cancer susceptibility, indicating that BARD1 may be involved in mediating tumour suppression by BRCA1."
    explanation: Original identification of BARD1 as the BRCA1 RING partner, linking the interaction to tumor suppression.
  - reference: PMID:37688570
    reference_title: BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we used CRISPR-Cas9 to generate isogenic neuroblastoma (IMR-5) and control (RPE1) cellular models harboring heterozygous BARD1 loss-of-function variants (R112*, R150*, E287fs, and Q564*)"
    explanation: Engineered heterozygous truncating alleles model the germline first hit without a second hit.
  gene:
    preferred_term: BARD1
    term:
      id: hgnc:952
      label: BARD1
  molecular_functions:
  - preferred_term: BRCA1-BARD1 heterodimer ubiquitin protein ligase activity
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
    modifier: DECREASED
  genetic_context:
    gene:
      preferred_term: BARD1
      term:
        id: hgnc:952
        label: BARD1
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Impaired BRCA1-BARD1 Homologous Recombination
    description: Reduced BARD1 dosage lowers BRCA1-BARD1-dependent RAD51 loading and homologous recombination; heterozygous isogenic cells already show the defect.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37688570
      reference_title: BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "BARD1 loss-of-function variant isogenic cells exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA double-strand break sites"
      explanation: Heterozygous engineered cells directly link a single germline-type allele to defective RAD51-dependent repair.
- name: Somatic BARD1 Second-Hit Inactivation
  description: >-
    Loss of the wild-type BARD1 allele is documented in a subset of carrier tumors but has not been shown to be universal. In a French case-control study, two of seven interpretable carrier breast tumors (both triple-negative primaries) showed loss of heterozygosity with an HRD phenotype, a metastasis showed LOH without HRD, and non-triple-negative primaries had neither. In a child with a germline BARD1 frameshift and refractory neuroblastoma, mono-allelic expression of the variant and loss of BARD1 protein on immunohistochemistry indicated biallelic loss in the tumor.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  evidence:
  - reference: PMID:42496958
    reference_title: "BARD1 and breast cancer genetic predisposition: case-control study and HRD signature analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these, two triple-negative (TN) primary tumors exhibited both biallelic BARD1 inactivation via loss of heterozygosity (LOH) and an HRD phenotype; one metastasis displayed LOH without HRD. All non-TN primary tumors lacked both biallelic inactivation and HRD."
    explanation: Tumor analysis of carrier breast cancers shows the second hit in triple-negative primaries and its absence in non-triple-negative primaries; seven tumors only.
  - reference: PMID:39141861
    reference_title: Response to PARP Inhibition in BARD1-Mutated Refractory Neuroblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemical staining of serial BM samples, obtained before talazoparib administration, confirmed somatic BARD1 protein loss"
    explanation: Single pediatric case documenting tumor-restricted loss of BARD1 protein in a germline heterozygote.
  genetic_context:
    gene:
      preferred_term: BARD1
      term:
        id: hgnc:952
        label: BARD1
    variant_origin: SOMATIC
    functional_impact_category: LOSS_OF_FUNCTION
    description: Loss of heterozygosity or other inactivation of the remaining allele in a subset of carrier-associated tumors.
  downstream:
  - target: Impaired BRCA1-BARD1 Homologous Recombination
    description: Biallelic loss in the tumor removes residual BRCA1-BARD1 function; in breast tumors it co-occurred with an HRD phenotype.
    causal_link_type: DIRECT
- name: Impaired BRCA1-BARD1 Homologous Recombination
  description: >-
    BRCA1-BARD1 binds DNA and RAD51 and stimulates RAD51-mediated synaptic-complex assembly during homologous recombination. BARD1 variants that are non-functional in homology-directed-repair reporter assays sensitize cells to ionizing radiation and cisplatin, and this assay separates known pathogenic from known benign BARD1 variants.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: "dna_repair_synthetic_lethality#HRR or FA/BRCA Repair Deficiency"
  evidence:
  - reference: PMID:28976962
    reference_title: BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51."
    explanation: Purified-protein biochemistry defines a direct BARD1-dependent step in homologous recombination.
  - reference: PMID:30925164
    reference_title: Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants."
    explanation: Cell-based HDR assays align loss of repair function with clinical pathogenicity.
  biological_processes:
  - preferred_term: double-strand break repair via homologous recombination
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
    modifier: DECREASED
  downstream:
  - target: Genomic Instability and Homologous-Recombination Deficiency
    description: Failure of error-free double-strand break repair increases DNA damage burden and chromosomal instability.
    causal_link_type: DIRECT
  - target: PARP-Inhibitor and Platinum Sensitivity
    description: HR-deficient cells become sensitive to PARP inhibition and cisplatin.
    causal_link_type: DIRECT
- name: Genomic Instability and Homologous-Recombination Deficiency
  description: >-
    Common and rare neuroblastoma-associated BARD1 germline variants were associated with lower BARD1 mRNA and higher DNA-damage burden. Bard1-null mouse cells are aneuploid, and mammary-specific Bard1 inactivation produces tumors with high chromosomal instability. HRD has been observed in triple-negative carrier breast tumors with LOH but not in non-triple-negative primaries.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  conforms_to: "genome_instability_mutation#Mutator Phenotype and Chromosomal Instability"
  evidence:
  - reference: PMID:37688570
    reference_title: BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both common and rare neuroblastoma-associated BARD1 germline variants were associated with lower levels of BARD1 mRNA and an increased burden of DNA damage."
    explanation: Genotype-correlation analysis in normal tissues and neuroblastomas links germline BARD1 variation to DNA damage burden.
  - reference: PMID:12832489
    reference_title: "Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This result, together with the increased chromosomal aneuploidy of Bard1 mutant cells, indicates a role for Bard1 in maintaining genomic stability."
    explanation: Complete Bard1 loss in mice causes aneuploidy; this is a null model, not the heterozygous human state.
  downstream:
  - target: Breast carcinoma
    description: Genomic instability in mammary epithelium is the proposed route to the ER-negative and triple-negative breast cancers enriched in carriers.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18443292
      reference_title: The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are \"triple negative\" for estrogen and progesterone receptor expression and HER2/neu amplification."
      explanation: Conditional mammary Bard1 inactivation produces triple-negative carcinomas; this is mouse evidence from a biallelic conditional deletion, not a heterozygous germline model.
  - target: Neuroblastoma
    description: DNA-repair infidelity is proposed by the primary authors as a mechanism contributing to neuroblastoma initiation in carriers.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37688570
      reference_title: BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Taken together, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications."
      explanation: The authors' conclusion links the repair defect to initiation; the initiation step itself was not tested directly.
- name: PARP-Inhibitor and Platinum Sensitivity
  description: >-
    Heterozygous BARD1 loss-of-function isogenic neuroblastoma cells show increased sensitivity to cisplatin and PARP inhibition in vitro and in vivo. This is a therapeutic vulnerability, not a disease manifestation; clinical evidence is a single pediatric case report.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  conforms_to: "dna_repair_synthetic_lethality#PARP and Platinum Synthetic Lethality"
  evidence:
  - reference: PMID:37688570
    reference_title: BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "enhanced sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo"
    explanation: Isogenic heterozygous models establish the drug sensitivity in cells and in vivo.
discussions:
- discussion_id: bard1_ovarian_cancer_disputed
  kind: CONTROVERSY
  attaches_to:
  - disease#
  prompt: Do germline BARD1 loss-of-function variants increase ovarian cancer risk?
  rationale: >-
    Most case-control data do not support an ovarian association, and ClinGen curated BARD1 and familial ovarian cancer (MONDO:0016248) as a separate gene-disease pair classified Disputed. One study (Norquist 2016) reported BARD1 variants as more common in ovarian carcinoma than in population databases, cautioning that two of its BARD1 carriers also carried BRCA1 variants. Ovarian cancer is therefore not recorded as a phenotype of this entry.
  evidence:
  - reference: CGGV:assertion_02af8326-360e-4f42-a378-fefff7387d97-2024-08-29T170000.000Z
    reference_title: BARD1 / familial ovarian cancer (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: "In summary, the evidence supporting the relationship between BARD1 and autosomal dominant hereditary ovarian cancer has been disputed and no valid evidence remains to support the claim."
    explanation: ClinGen's separate ovarian curation disputes the association.
  - reference: PMID:32679805
    reference_title: Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "but not an OC risk gene (OR = 1.36, 95% CIs:0.87-2.11, p = 0.1733)"
    explanation: Pooled analysis of about 20,800 ovarian cancer cases against gnomAD controls found no significant ovarian association.
  - reference: PMID:26315354
    reference_title: "Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "but no differences for BARD1 (P = .39)"
    explanation: Case-control sequencing of invasive epithelial ovarian cancer found no difference in BARD1 deleterious-variant frequency between cases and controls.
  - reference: PMID:31036035
    reference_title: Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC."
    explanation: No carriers among familial ovarian cancer index patients in GC-HBOC.
  - reference: PMID:26720728
    reference_title: Inherited Mutations in Women With Ovarian Carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1 mutations were rare in OC patients, but significantly more common than in the general population, leading to wide confidence intervals for the generated odds ratio for OC (Table 2)."
    explanation: The one study reporting an ovarian enrichment, against population databases rather than matched controls.
  - reference: PMID:26720728
    reference_title: Inherited Mutations in Women With Ovarian Carcinoma.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "These results are interpreted with some caution as two of the BARD1 mutation carriers also had mutations in BRCA1 (eTable1)."
    explanation: The same study notes that two of its BARD1 carriers also carried BRCA1 variants, weakening its own ovarian signal.
- discussion_id: bard1_neuroblastoma_common_vs_rare
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Neuroblastoma
  prompt: How large is the neuroblastoma risk for a heterozygous BARD1 loss-of-function carrier, and should carriers be surveilled in childhood?
  rationale: >-
    Two signals must be kept apart. Common BARD1 polymorphisms at 2q35 are associated with high-risk neuroblastoma in GWAS; this is polygenic susceptibility, not this Mendelian entity. Separately, rare germline pathogenic or likely pathogenic BARD1 variants and BARD1-disrupting copy-number variants are enriched in neuroblastoma patients, and ClinGen lumps neuroblastoma into this entity on that case-control evidence. The case-control odds ratios are wide (OR 32.30, 95% CI 6.44 to 310.35 in 786 patients; OR 6.3, 95% CI 2.4 to 13.9 in a pediatric pan-cancer analysis whose cohort overlap with the first study was not assessed here). Absolute childhood penetrance is not reported in these sources, and no source used here gives a neuroblastoma surveillance recommendation for carrier children.
  evidence:
  - reference: PMID:19412175
    reference_title: Common variations in BARD1 influence susceptibility to high-risk neuroblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma."
    explanation: The GWAS signal concerns common variants and is outside this Mendelian entity.
  - reference: PMID:38411636
    reference_title: "Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma."
    explanation: Review framing of BARD1 as an adult-onset predisposition gene with a pediatric tumor association, which leaves testing and surveillance of children an open question.
- discussion_id: bard1_biallelic_phenotype_unknown
  kind: KNOWLEDGE_GAP
  attaches_to:
  - inheritance#Autosomal dominant
  prompt: Is there a constitutional biallelic BARD1 phenotype in humans?
  rationale: >-
    Bard1-null mice die between E7.5 and E8.5, and a 2022 review states that BARD1 is not a classic Fanconi anemia gene. A PubMed search, BARD1[ti] AND (biallelic[tiab] OR homozygous[tiab] OR compound heterozygous[tiab]), returned six records, none of which describes a person with constitutional biallelic BARD1 variants. Whether biallelic loss is compatible with human development, and with what phenotype, is unknown.
  evidence:
  - reference: PMID:12832489
    reference_title: "Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice become developmentally retarded and die between embryonic day 7.5 (E7.5) and E8.5."
    explanation: Constitutional Bard1 nullizygosity is early embryonic lethal in mice.
  - reference: PMID:35772246
    reference_title: "Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM, CHEK2, BARD1 and RAD51D."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "No data are available regarding reproductive implications. BARD1 is not a classic FA gene."
    explanation: Review statement that no biallelic Fanconi-like syndrome is established for BARD1.
phenotypes:
- category: Neoplastic
  name: Breast carcinoma
  description: >-
    Female breast cancer is the established manifestation, at moderate risk. In BCAC (protein-truncating variants) the overall odds ratio in population-based studies was 2.09 (95% CI 1.35 to 3.23), with estimated absolute risk by age 80 in the 17 to 30% moderate-risk range; in the population-based CARRIERS study the overall odds ratio was 1.37 (95% CI 0.87 to 2.16), not significant. Both consortia found stronger associations with estrogen-receptor-negative disease. In familial German index patients, carriers were diagnosed younger (mean 42.3 years) and the association was not significant at age 50 or older.
  phenotype_term:
    preferred_term: Breast carcinoma, enriched for estrogen-receptor-negative and triple-negative subtypes
    term:
      id: HP:0003002
      label: Breast carcinoma
  evidence:
  - reference: CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z
    reference_title: BARD1 / BARD1-related cancer predisposition (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BARD1-related cancer predisposition is characterized by a susceptibility to breast cancer with emerging evidence suggesting the association of other cancer types including neuroblastoma."
    explanation: ClinGen names breast cancer as the defining manifestation of this entity.
  - reference: PMID:33471991
    reference_title: "Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1 (odds ratio, 2.09; 95% CI, 1.35 to 3.23; P = 0.00098 [P = 0.00011 in all studies])"
    explanation: BCAC overall breast cancer odds ratio for protein-truncating BARD1 variants in population-based studies.
  - reference: PMID:33471991
    reference_title: "Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For carriers of protein-truncating variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D, the estimated absolute risks by 80 years of age were within the 17 to 30% range for moderate risk"
    explanation: Absolute-risk estimate placing BARD1 in the moderate-risk category, derived from UK incidences.
  - reference: PMID:33471991
    reference_title: "Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, for BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative breast cancer than for ER-positive breast cancer (P<0.05 for all genes)."
    explanation: BCAC subtype analysis shows ER-negative predominance.
  - reference: PMID:33471974
    reference_title: A Population-Based Study of Genes Previously Implicated in Breast Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer"
    explanation: CARRIERS population-based case-control analysis supports a subtype-restricted association.
  - reference: PMID:33471974
    reference_title: A Population-Based Study of Genes Previously Implicated in Breast Cancer.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1 | 49 (0.15) | 35 (0.11) | 1.37 (0.87–2.16) | 0.18"
    explanation: The CARRIERS overall (all-subtype) association did not reach significance; recorded so the overall risk is not overstated.
  - reference: PMID:30099541
    reference_title: Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1 (OR = 5.92, 95% CI = 3.36 to 10.27, P = 2.2×10-9)"
    explanation: Triple-negative breast cancer association in a clinically tested Caucasian cohort compared with reference controls.
  - reference: PMID:31036035
    reference_title: Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347)."
    explanation: Earlier onset among familial carriers; a selected familial cohort, not population penetrance.
  phenotype_contexts:
  - sex: FEMALE
    population: German Consortium for Hereditary Breast and Ovarian Cancer familial index patients, BRCA1/2-negative
    notes: Association concentrated in early-onset disease; OR 12.04 below age 40 and not significant at age 50 or older.
    evidence:
    - reference: PMID:31036035
      reference_title: Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed."
      explanation: Age-stratified estimate for the youngest group.
    - reference: PMID:31036035
      reference_title: Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217)."
      explanation: Age-stratified estimate for the oldest group.
- category: Neoplastic
  name: Neuroblastoma
  description: >-
    Rare germline pathogenic or likely pathogenic BARD1 variants were the most significantly enriched cancer-predisposition-gene finding among 786 neuroblastoma patients, and rare germline copy-number variants disrupting BARD1 were found in patients but not in cancer-free controls. A pediatric pan-cancer germline analysis also found the BARD1-neuroblastoma association (6 of 485 neuroblastoma cases). Absolute penetrance in carriers is not reported in these sources. The one case report used here describes metastatic high-risk neuroblastoma diagnosed at 22 months.
  phenotype_term:
    preferred_term: Neuroblastoma
    term:
      id: HP:0003006
      label: Neuroblastoma
  evidence:
  - reference: PMID:37688579
    reference_title: Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35)."
    explanation: Case-control germline sequencing of 786 neuroblastoma patients against cancer-free controls.
  - reference: PMID:37688579
    reference_title: Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70)."
    explanation: Copy-number loss-of-function alleles show the same direction of association.
  - reference: PMID:41066719
    reference_title: Investigation of DNA Damage Response Genes Validates the Role of DNA Repair in Pediatric Cancer Risk and Identifies SMARCAL1 as a Novel Osteosarcoma Predisposition Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1 | NBL | 6 in 485 (1.24%) | 31 in 14,477 (0.21%) | 6.3 (2.4 to 13.9)"
    explanation: Pediatric cancer germline case-control analysis against adult noncancer controls; possible cohort overlap with the 786-patient study was not assessed.
  - reference: CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z
    reference_title: BARD1 / BARD1-related cancer predisposition (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Therefore, breast cancer and neuroblastoma have been lumped into this curation."
    explanation: ClinGen includes neuroblastoma in this entity under its lumping and splitting criteria.
  - reference: PMID:39141861
    reference_title: Response to PARP Inhibition in BARD1-Mutated Refractory Neuroblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was diagnosed at 22 months with metastatic HRNBL."
    explanation: Single case documenting early-childhood onset in one germline heterozygote; not an onset distribution.
genetic:
- name: BARD1
  variant_origin: GERMLINE
  gene_term:
    preferred_term: BARD1
    term:
      id: hgnc:952
      label: BARD1
  relationship_type: CAUSATIVE
  notes: >-
    Pathogenic alleles are mainly truncating, splice and copy-number variants; some missense variants in the ankyrin-repeat and BRCT domains are non-functional in homology-directed-repair assays. Carrier frequency among CARRIERS population-based controls was 35 of 32,544 (0.11%). ClinGen separately classifies BARD1 and familial ovarian cancer (MONDO:0016248) as Disputed; that tier is not recorded here because it concerns a different disease.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z
    evidence:
    - reference: CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z
      reference_title: BARD1 / BARD1-related cancer predisposition (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "BARD1 | HGNC:952 | BARD1-related cancer predisposition | MONDO:0700267 | AD | Definitive"
      explanation: ClinGen Hereditary Cancer GCEP classification for this MONDO entity.
  evidence:
  - reference: CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z
    reference_title: BARD1 / BARD1-related cancer predisposition (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BARD1 | HGNC:952 | BARD1-related cancer predisposition | MONDO:0700267 | AD | Definitive"
    explanation: ClinGen Definitive gene-disease validity for BARD1 in this entity.
  - reference: PMID:32679805
    reference_title: Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The analysis revealed that BARD1 is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25-3.75, p < 0.0001)"
    explanation: Pooled analysis of about 48,700 breast cancer cases from 123 studies.
  - reference: PMID:30925164
    reference_title: Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR."
    explanation: Functional evidence that missense variants outside the RING domain can abolish repair activity.
  - reference: PMID:33471974
    reference_title: A Population-Based Study of Genes Previously Implicated in Breast Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BARD1 | 49 (0.15) | 35 (0.11) | 1.37 (0.87–2.16) | 0.18"
    explanation: Source of the population-control carrier frequency (35 of 32,544 controls).
diagnosis:
- name: Germline molecular diagnosis
  description: >-
    Identification of a heterozygous pathogenic or likely pathogenic germline BARD1 variant, usually on a hereditary breast cancer multigene panel; BARD1 variants are also found through paired tumor-normal sequencing of children with neuroblastoma. Missense variants of uncertain significance are common and can be informed by functional HDR assays.
  evidence:
  - reference: PMID:42496958
    reference_title: "BARD1 and breast cancer genetic predisposition: case-control study and HRD signature analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a strong enrichment of BARD1 gPV among women selected for personal and family history of breast cancer, reinforcing their relevance for genetic testing for suspected hereditary predisposition."
    explanation: Supports inclusion of BARD1 in hereditary breast cancer panel testing.
  - reference: PMID:39141861
    reference_title: Response to PARP Inhibition in BARD1-Mutated Refractory Neuroblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Paired tumor-normal whole-exome analysis identified a pathogenic germline heterozygous frameshift in BARD1, but no other known driver variants"
    explanation: Paired tumor-normal sequencing in pediatric oncology is a second ascertainment route.
treatments:
- name: Breast cancer surveillance
  description: >-
    A 2022 review table adapted from NCCN v2.2022 lists annual mammography (tomosynthesis) and contrast-enhanced breast MRI starting at age 40, and states that evidence is insufficient for risk-reducing mastectomy, which is managed by family history. The primary GC-HBOC study recommends intensified surveillance on the basis of its early-onset association. Current NCCN text was not checked directly for this entry.
  treatment_term:
    preferred_term: breast cancer screening with mammography and breast MRI
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:35772246
    reference_title: "Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM, CHEK2, BARD1 and RAD51D."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BARD1 | ● Limited emerging evidence to suggest increased risk of female BC (with predisposition to triple negative) ● Unknown or Insufficient evidence for OC or other cancers risk | ● RRM: evidence insufficient, manage based on family history ● Screening: annual mammogram (tomosythesis) and breast MRI with contrast starting at age 40"
    explanation: Review table reproducing NCCN v2.2022 management for BARD1, including the absence of an ovarian or other-cancer recommendation.
  - reference: PMID:31036035
    reference_title: Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants."
    explanation: Primary-study recommendation for surveillance in carriers.
  target_mechanisms:
  - target: Breast carcinoma
    description: Surveillance detects breast cancer earlier; it does not modify the underlying mechanism.
- name: Genetic counseling and cascade testing
  description: >-
    Counseling covers the moderate breast cancer risk, the disputed ovarian association, and the pediatric neuroblastoma association, for which no surveillance recommendation is given in the sources used here. Testing minors for an adult-onset predisposition gene with a pediatric tumor association is an open question.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38411636
    reference_title: "Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Examples include heterozygous PVs in BRCA1, RAD51C or BARD1 in childhood neuroblastoma"
    explanation: Review placing BARD1 among adult-onset predisposition genes found in children with cancer, relevant to pediatric counseling.
- name: Talazoparib in BARD1-associated refractory neuroblastoma
  description: >-
    One child with a germline BARD1 frameshift, somatic BARD1 protein loss and refractory high-risk neuroblastoma had a complete bone-marrow response to talazoparib plus irinotecan and remained without clinical evidence of disease 32 months off therapy. This is a single case report plus preclinical data, not an established indication.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: PARP inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: talazoparib
      term:
        id: CHEBI:231344
        label: talazoparib
  evidence:
  - reference: PMID:39141861
    reference_title: Response to PARP Inhibition in BARD1-Mutated Refractory Neuroblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first response of a child with neuroblastoma and a BARD1 germline mutation to a PARPi."
    explanation: Single pediatric case report of response.
  - reference: PMID:39141861
    reference_title: Response to PARP Inhibition in BARD1-Mutated Refractory Neuroblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is 32 months off therapy with no clinical evidence of disease"
    explanation: Durability in the single reported case.
  target_mechanisms:
  - target: PARP-Inhibitor and Platinum Sensitivity
    description: Exploits the homologous-recombination defect of BARD1-deficient tumor cells.
animal_models:
- name: Mammary-conditional Bard1 knockout mouse
  species: Mus musculus
  genotype: Conditional Bard1 alleles inactivated by Cre in mammary epithelial cells
  publication: PMID:18443292
  description: >-
    Mammary-specific Bard1 inactivation produced carcinomas indistinguishable from conditional Brca1 and double-mutant tumors in frequency, latency, histopathology and cytogenetics. The tumors were triple-negative and basal-like. The model is biallelic and tissue-restricted, not a heterozygous germline model.
  evidence:
  - reference: PMID:18443292
    reference_title: The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Significantly, the conditional Bard1- and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional Bard1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features."
    explanation: Equivalence of Bard1 and Brca1 tumors supports a heterodimer-mediated tumor-suppressor function.
  modeled_mechanisms:
  - target: Genomic Instability and Homologous-Recombination Deficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reproduces chromosomally unstable triple-negative mammary carcinoma after Bard1 loss.
    limitations: Biallelic conditional deletion in mammary epithelium; does not model the heterozygous germline state or the neuroblastoma association.
    evidence:
    - reference: PMID:18443292
      reference_title: The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability."
      explanation: Tumor cytogenetics show chromosomal instability.
- name: Bard1-null mouse
  species: Mus musculus
  genotype: Bard1 homozygous null
  publication: PMID:12832489
  description: >-
    Constitutional Bard1 nullizygosity is lethal between E7.5 and E8.5 owing to impaired proliferation, partly ameliorated by p53 loss; mutant cells are aneuploid.
  evidence:
  - reference: PMID:12832489
    reference_title: "Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The striking similarities between the phenotypes of Bard1-null, Brca1-null, and double Bard1; Brca1-null mice provide strong genetic evidence that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer."
    explanation: Genetic evidence that Bard1 acts through the Brca1/Bard1 heterodimer.
  modeled_mechanisms:
  - target: Germline BARD1 Loss of Function
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    description: Complete constitutional loss of Bard1.
    limitations: Homozygous null and embryonic lethal; informs gene function, not the heterozygous human cancer predisposition.
    evidence:
    - reference: PMID:12832489
      reference_title: "Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To explore the genetic relationship between BRCA1 and BARD1, we have examined the phenotype of Bard1-null mice."
      explanation: The model removes Bard1 entirely.

📚

References & Deep Research

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: BARD1-related_Cancer_Predisposition · 2026-10-13T20:35:03Z · View source

Created the entry for MONDO:0700267 from primary literature, the cached ClinGen gene-disease validity records, and one deep-research report used only as a lead. Falcon (Edison) was the assigned deep-research provider but failed twice with '503 Failed to authenticate' before any provider task was created (once at 20:16 UTC and again after a ten-minute wait); no falcon report exists. One claude_code report was run instead (research/BARD1-related_Cancer_Predisposition-deep-research-claude_code.md). That report did not find the ClinGen assertion, treated the 2023 haploinsufficiency preprint as unpublished (it is PMID:37688570), and said no human two-hit data existed; each of those was checked against primary sources and superseded. Its secondary sources (payer policy, NSGC news item, FORCE, NHS Genomics Education, Rofes 2021) were not cited. Lump/split: ClinGen (CGGV assertion 09113d8c, Definitive, AD, Hereditary Cancer GCEP, 2024) lumps breast cancer and neuroblastoma into MONDO:0700267 and curates BARD1-familial ovarian cancer (MONDO:0016248) separately as Disputed (CGGV assertion 02af8326). The entry follows that: breast carcinoma and neuroblastoma are phenotypes; ovarian cancer is a CONTROVERSY discussion with REFUTE evidence (ClinGen, Suszynska 2020 pooled OR, Ramus 2015, Weber-Lassalle 2019) and the one supporting study (Norquist 2016) with its BRCA1 co-carrier caveat. Common-variant 2q35 GWAS susceptibility to neuroblastoma (Capasso 2009) is recorded only as a boundary in a knowledge-gap discussion, not as a phenotype. No constitutional biallelic BARD1 phenotype was found (PubMed query recorded in the discussion); recorded as a knowledge gap. Pathograph: germline BARD1 LOF (GO:0061630 ubiquitin protein ligase activity, decreased) and somatic second hit -> impaired BRCA1-BARD1 homologous recombination (GO:0000724) -> genomic instability/HRD -> breast carcinoma and neuroblastoma; HR defect -> PARP/platinum sensitivity (talazoparib case report). Conformance declared to germline_two_hit_tumor_predisposition, dna_repair_synthetic_lethality and genome_instability_mutation nodes. Validation: just validate, count-verified-snippets (56/56), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-genereviews (no GeneReviews chapter in the 2026-09-10 index), list-gene-term-mismatches, check-block-scalar-comments, the whole-KB ungated gates, the gene-activity grounding script, and validate-disorders. Gaps: no GeneReviews chapter; current NCCN text not read directly (surveillance cites a 2022 review table adapted from NCCN v2.2022); absolute neuroblastoma penetrance and any pediatric surveillance recommendation not found; possible cohort overlap between the two neuroblastoma case-control studies not assessed; preflight-dr could not run (no local mondo.db, exit 2).

Claude Code ▸

BARD1-related Cancer Predisposition: research report

claude-haiku-5-5, claude-sonnet-5-5 11 citations 2026-10-13T20:28:44.520655

BARD1-related Cancer Predisposition: research report

Read this first. I ran four web searches in this session. Anything marked [searched] comes from those results. Mostly that is search-result abstracts and snippets, and I did not open the full texts. Anything marked [memory] is background recall with no source checked in this run. Treat it as a lead and verify it before it goes into a KB entry. I did not write any PMIDs from memory, because an unchecked PMID is a defect under this repo's rules. Where I have a source, I give the DOI or PMC ID that appeared in the results. The MONDO ID in the template (MONDO:0700267), the OMIM, Orphanet and ClinGen identifiers, and the HP/GO/CL/UBERON/NCIT term suggestions were not looked up. Do not bind any of them until they are read from the ontology.

Scope and lump/split calls

This entry is the germline predisposition syndrome. It should stay separate from the somatic breast, ovarian and neuroblastoma entries it predisposes to (design-decisions §3a).
Lump/split call 1. Adult breast cancer predisposition (moderate-penetrance, heterozygous) and the proposed pediatric neuroblastoma predisposition are different clinical entities with different evidence strength. I would keep one germline entry, with the two as separate phenotype arms. The pediatric arm would be flagged as lower-confidence unless a ClinGen or guideline source supports it. A split into two entries is defensible.
Lump/split call 2. OMIM carries a neuroblastoma susceptibility locus, "Neuroblastoma, Susceptibility To, 5" [searched: findzebra listing only; OMIM number not verified]. Whether this and the breast predisposition belong in one disorder is unresolved.
The Mendelian lane also needs an explicit decision on biallelic BARD1. I found no source on it in this session.

1. Disease information

BARD1 encodes the obligate heterodimer partner of BRCA1. The heterodimer has E3 ubiquitin ligase activity and acts in homologous recombination repair. [memory]
Heterozygous germline loss-of-function variants confer moderate-penetrance breast cancer risk, with an apparently stronger association with triple-negative disease. The clinical framing is "BRCA1-like partner, but lower penetrance" [memory].
Identifiers and synonyms: not retrieved. The MONDO ID given in the template is unverified. HGNC for BARD1 is not looked up. Neuroblastoma susceptibility 5 appears in a findzebra listing [searched], but I did not verify the OMIM number.
Data source class: aggregated cohort and case-control resources (germline sequencing series, gnomAD-controlled comparisons), not EHR-derived.

2. Etiology

Causal factor. Heterozygous germline BARD1 pathogenic variants, mostly truncating [memory].
Breast cancer risk estimate [searched].
Source class: primary literature, single cohort. Rofes et al., Genes 2021, DOI 10.3390/genes12020150 (PMC7911518), a Spanish hereditary breast and ovarian cancer cohort of 4,015 patients compared with gnomAD controls.
Truncating variants overall: OR 3.78 (95% CI 2.10–6.48; p = 1.16 × 10⁻⁵).
Hereditary breast cancer group: OR 4.18 (95% CI 2.10–7.70).
Triple-negative breast cancer (TNBC) enrichment versus other subtypes: OR 5.40 (95% CI 1.77–18.15; p = 0.001).
The authors conclude BARD1 is a moderate-penetrance breast cancer gene with a stronger TNBC association.
A payer policy summary states BARD1 variants confer about 2–3× general-population breast cancer risk [searched: payer document, not primary]. This is lower than the single-cohort OR above. The two estimates differ in design and are not directly comparable.
Large consortium estimates (Dorling and CARRIERS/BCAC-type studies, and the Weber-Lassalle series) were not retrieved. My search for them returned nothing relevant. Those are the primary sources the entry should cite for effect sizes.
Pediatric arm: neuroblastoma [searched].
Common-variant GWAS: Capasso et al. 2009, Nat Genet. Six SNPs at 2q35 in the BARD1 locus associated with high-risk neuroblastoma (397 cases/2,043 controls, replicated in 189 cases/1,178 controls). Source class: primary literature, common-variant association. It does not establish a high-penetrance Mendelian effect.
Rare-variant enrichment: a cohort of 786 patients reported BARD1 as the most significantly enriched gene for pathogenic or likely pathogenic germline variants (OR 32.30; 95% CI 6.44–310.35), and linked germline P/LP variants to worse overall survival. Source class: primary literature, cohort. I saw only an abstract snippet, and the confidence interval is very wide.
A bioRxiv preprint (2023) reports that common and rare neuroblastoma-associated BARD1 variants lower BARD1 mRNA and increase DNA damage, and that BARD1-LoF isogenic cells repair Cas9-induced damage less efficiently. Source class: preprint, not peer-reviewed in this retrieval. Check whether a peer-reviewed version exists.
Environmental and protective factors: no BARD1-specific sources found. Do not import BRCA1/2 assumptions. Gene-environment interaction: no data retrieved.

3. Phenotypes

Everything below is [memory] unless stated. Frequencies and HPO bindings need checking against HPO, Orphanet and the primary literature.

Phenotype	Notes
Breast carcinoma, adult onset	Main phenotype. Triple-negative subtype enriched [searched, Rofes 2021].
Neuroblastoma, childhood	Susceptibility arm; high-risk subset in the GWAS [searched].
Ovarian, pancreatic and other cancers	Weaker, uncertain. I did not retrieve sources.

There is no known non-cancer syndromic phenotype. Do not invent a quality-of-life section; I have no data.
Pediatric framing: onset age and penetrance for the neuroblastoma arm are not established in what I retrieved. Say so in the entry rather than imply a childhood surveillance indication.

4. Genetic and molecular information

Gene: BARD1, chromosome 2q35. 2q35 is [searched] (Capasso GWAS). The HGNC ID (lowercase hgnc: form in this repo) must be looked up.
Variants: mostly truncating or LoF. Missense variants in the RING and BRCT domains are largely VUS [memory]. Interpretation of missense variants is a known difficulty. I have no sourced classification data.
Origin: germline. Mechanism: haploinsufficiency is supported for neuroblastoma-associated variants by the preprint [searched]. For breast cancer, LoF is the working model [memory].
ClinGen validity: not found in my search, so no gene_disease_validity assertion can be copied. Check just genes-clingen-gaps and the cached CGGV records before writing one. Do not assign a tier.
Modifier genes, epigenetics, chromosomal abnormalities: nothing retrieved.

5. Environmental information

None BARD1-specific retrieved. Leave environmental blocks empty rather than borrowing from BRCA1.

6. Mechanism (ordered causal chain)

A germline heterozygous LoF variant in BARD1 reduces BARD1 dosage. Haploinsufficiency is demonstrated in neuroblastoma-variant cell and expression data [searched, preprint]. It is inferred for breast cancer.
Reduced BARD1 destabilises or reduces the BRCA1–BARD1 heterodimer, which is [memory], mechanistically expected but not sourced here.
The result is a homologous recombination repair defect and increased DNA damage. The preprint supports reduced repair of Cas9-induced damage in BARD1-LoF cells [searched, in vitro].
Unrepaired damage and genomic instability follow. This is supported in mouse by McCarthy et al. 2003 (Mol Cell Biol; PMC162231 appeared in results): Bard1-null embryos die at E7.5–E8.5 from impaired proliferation, and mutant cells show increased aneuploidy [searched]. Evidence source: model organism.
Loss of the second allele or other cooperating events leads to tumour initiation. The two-hit step in human carriers is inferred, not shown in anything I retrieved.
The tissue pattern is breast, with a TNBC bias, and neuroblastoma in the pediatric arm. In mouse, mammary-specific conditional Bard1 loss produces basal-like mammary carcinomas with frequency, latency and histology indistinguishable from conditional Brca1 loss [searched; snippet only, the paper identity is "likely Shakya et al. 2008", unconfirmed]. This parallels the human TNBC enrichment. It is a model-organism result and the mouse is a full conditional knockout, not a heterozygous germline model.

Suggested GO/CL terms for this chain would be DNA repair and homologous recombination, ubiquitin ligase activity, and mammary epithelial cell and sympathetic neuroblast lineages. All are unverified and need ontology lookup.

7. Anatomical structures

Breast (mammary epithelium) and the sympathetic nervous system or adrenal medulla (neuroblastoma). Ovary is uncertain. No lateralisation data retrieved. UBERON/CL bindings: not looked up.

8. Temporal development

Breast: adult onset. Specific age distribution not retrieved.
Neuroblastoma: infancy to early childhood, as is general for the tumour [memory]. The age at diagnosis for BARD1 carriers specifically was not retrieved.

9. Inheritance and population

Autosomal dominant with reduced penetrance [memory].
Population frequency, founder variants, carrier frequency, sex ratio: not retrieved. gnomAD was used as the control set in the Rofes study [searched].
Penetrance numbers: only the 2–3× relative-risk statement [searched, payer document] and the OR above. Absolute lifetime risk was not retrieved. The UK genomics hub text mentions a ≥30% estimated lifetime risk as a threshold for considering mastectomy [searched], which is a decision threshold and not a BARD1-specific penetrance figure.

10. Diagnostics

Multigene hereditary cancer panel testing. BARD1 is included on common panels [memory].
No BARD1-specific biomarker, imaging, or histology criteria retrieved, though TNBC histology is a reported association [searched].
Variant interpretation: no ClinGen VCEP or ACMG-specific BARD1 guidance retrieved.

11. Prognosis

Not retrieved for adult breast carcinoma. For neuroblastoma, one cohort linked germline P/LP variants to worse overall survival [searched, abstract snippet].

12. Treatment and surveillance

Surveillance: NCCN recommends annual mammogram and breast MRI from age 40 for carriers of BARD1, RAD51C and RAD51D [searched; quoted in an NSGC news item, secondary source. Verify against the NCCN guideline itself, which I did not open].
Risk-reducing mastectomy: evidence described as insufficient or uncertain in several secondary sources (UK Genomics Education hub, FORCE, a payer summary) [searched]. The UK hub says it may be considered for higher-risk variants with an estimated lifetime risk of 30% or more.
PARP inhibitors: BARD1 carriers' response is not established in anything I retrieved. I did not search for it, so do not assert either way.
Candidate NCIT terms for surveillance and counselling procedures: not looked up. Use the repo's term-lookup workflow.
Clinical trials: none searched.

13. Prevention

Enhanced breast screening as above. No evidence found for chemoprevention. Cascade testing and genetic counselling apply generally [memory]. For children, I found no surveillance recommendation for neuroblastoma in BARD1 carriers. The entry should record that gap.

14–15. Other species and model organisms

Mouse: constitutive Bard1 knockout is embryonic lethal (E7.5–E8.5), delayed to about E9.5 when p53 is also removed [searched, McCarthy 2003, PMC162231]. Conditional mammary knockout gives basal-like carcinomas [searched, snippet; PMC2365565 appeared among results but I did not confirm it is that paper]. Conditional alleles exist (Columbia listing, MGI alleles MGI:2668394 and MGI:4939693 appeared in results, unverified).
Fidelity caveat for a modeled_mechanisms link: the null and conditional-null models do not reproduce the human heterozygous moderate-penetrance state. They support the BRCA1–BARD1 tumour-suppressor mechanism but only partially recapitulate the human phenotype.
Natural disease in other species, OMIA, zebrafish, Drosophila and cell lines: not searched.

Gaps to close before curation

Primary consortium effect sizes for breast cancer (BCAC/CARRIERS, Dorling, Weber-Lassalle). Not found in my search.
ClinGen gene-disease validity for BARD1 and its cached CGGV record.
Primary NCCN text, plus any ESMO/ACMG/ERN guidance.
Peer-reviewed status of the neuroblastoma preprint, and the exact citation for the 786-patient cohort.
Penetrance, ovarian and pancreatic risk, and tumour-spectrum data.
Identifiers: MONDO, OMIM, Orphanet, HGNC, and every HPO/GO/CL/UBERON/NCIT term.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	4
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	3
Resolved	1
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.

1 of 3 terms resolved to a current term; the rest could not be looked up either way.

BARD1-related Cancer Predisposition

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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

Deep Research

BARD1-related Cancer Predisposition: research report

Scope and lump/split calls

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism (ordered causal chain)

7. Anatomical structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Prognosis

12. Treatment and surveillance

13. Prevention

14–15. Other species and model organisms

Gaps to close before curation

Sources

Reference Validation

Term Validation

Prefixes with no resolver