BARD1 – Hereditary Breast Carcinoma

BARD1 encodes the BRCA1-associated RING domain protein, a critical heterodimeric partner of BRCA1 that mediates E3 ubiquitin ligase activity, homologous recombination–dependent DNA repair, cell cycle control, and mRNA processing in response to DNA damage (PMID:11278247; PMID:11257228). Biallelic loss of BARD1 is embryonic lethal in mice, underscoring its essential role in genome integrity. Heterozygous germline variants have been investigated as contributors to hereditary breast carcinoma risk since BARD1 stabilizes and colocalizes BRCA1 at sites of DNA damage.

Genetic evidence comes from multiple cohorts of BRCA1/2-negative and unselected patients. A Spanish hereditary breast cancer series (n = 4,015) identified truncating BARD1 variants in 19 patients (0.47% vs. 0.12% in controls; OR 4.18; p = 5.45 × 10⁻⁵) with enrichment in triple-negative tumors (PMID:33498765). In a Korean high-risk BRCA1/2–negative panel (n = 120), two pathogenic truncating variants were observed (PMID:29338689). Single heterozygous LoF variants including c.448C>T (p.Arg150Ter) were found in Guatemalan unselected breast cancer cases (1/664; 0.15%) (PMID:34196900), in a Brazilian familial cohort (p.Tyr739fs) (PMID:29868112), and in one Greek HBOC family (p.Trp91Ter) (PMID:31681433). This yields at least 24 unrelated probands with truncating or splice-site variants.

Inheritance is autosomal dominant with moderate penetrance. No robust segregation data are reported, and affected-relative counts remain limited. The variant spectrum is dominated by nonsense, frameshift, and splice-site mutations; recurrent missense alleles have not been clearly linked to risk. The splice-site variant c.1314+1G>A and frameshift c.157del (p.Cys53fs) have been reported but lack strong segregation. Population-specific founder alleles have not been established.

Functional assays have demonstrated that BARD1 loss-of-function disrupts BRCA1-mediated homologous recombination. Homology-directed repair assays of BARD1 missense variants revealed three HDR-defective and three intermediate-function substitutions mapping to the RING and BRCT domains, with impaired ubiquitin ligase activity upon BRCA1 binding (PMID:26350354). Cellular studies show that tumor-associated germline mutations (e.g., p.Gln564His) abrogate BRCA1/BARD1 complex formation, nuclear foci assembly, and mRNA 3′-processing control in response to genotoxic stress (PMID:11257228).

Conflicting evidence includes Japanese familial cases (n = 60) with no clearly deleterious BARD1 mutations and identification of six missense variants considered benign polymorphisms, indicating that germline BARD1 alterations account for a very small fraction of familial breast cancer (PMID:14550946). In Finnish cohorts, Cys557Ser and Val507Met showed no significant association with risk (PMID:16333312).

Overall, BARD1 meets ClinGen Moderate clinical validity, supported by ~24 probands across independent cohorts, significant case-control association, and concordant functional evidence demonstrating loss-of-function mechanism. While some missense variants lack pathogenicity, truncating and splice-site alleles confer moderate penetrance risk—informing genetic testing and risk management in hereditary breast carcinoma. Key take-home: incorporating BARD1 into multigene panels aids the identification of moderate-risk individuals for targeted surveillance and may guide future therapeutic strategies.

References

• Cell • 2001 • The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation PMID:11278247
• Cell • 2001 • The BARD1-CstF-50 interaction links mRNA 3′ end formation to DNA damage and tumor suppression PMID:11257228
• Cancer letters • 2003 • Mutational analysis of BARD1 in familial breast cancer patients in Japan. PMID:14550946
• BMC cancer • 2018 • Variants of cancer susceptibility genes in Korean BRCA1/2 mutation-negative patients with high risk for hereditary breast cancer. PMID:29338689
• Frontiers in genetics • 2019 • Exome Sequencing in BRCA1- and BRCA2-Negative Greek Families Identifies MDM1 and NBEAL1 as Candidate Risk Genes for Hereditary Breast Cancer. PMID:31681433
• Frontiers in genetics • 2018 • Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer. PMID:29868112
• Breast cancer research and treatment • 2021 • Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer. PMID:34196900
• Genes • 2021 • BARD1 Pathogenic Variants are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort. PMID:33498765
• Human mutation • 2015 • Functional Analysis of BARD1 Missense Variants in Homology-Directed Repair of DNA Double Strand Breaks. PMID:26350354

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