BARD1 – Breast Cancer

BARD1 encodes a BRCA1-associated RING domain protein essential for DNA repair and ubiquitination, acting as a tumor suppressor in breast epithelium (PMID:11257228). Heterozygous loss-of-function and select missense variants in BARD1 confer a moderate risk of breast cancer, particularly in ER-negative and triple-negative subtypes.

Large case–control and panel sequencing studies have demonstrated an increased breast cancer risk associated with BARD1 germline variants. In a multigene panel of 65 057 women, pathogenic BARD1 variants conferred an OR of 2.16 for breast cancer (PMID:28418444). A Central European study of ~14 000 unselected cases identified 38 carriers of the recurrent nonsense variant p.Gln564Ter (c.1690C>T), associated with OR = 2.30 (p = 0.04) (PMID:31142030). Subtype analysis in 54 555 invasive cases confirmed enrichment of BARD1 variants in ER-negative and triple-negative tumors (OR > 2) (PMID:32091585).

Inheritance is autosomal dominant; truncating alleles undergo somatic loss of the wild-type allele, consistent with a tumor suppressor mechanism. The variant spectrum includes nonsense (e.g., c.1690C>T (p.Gln564Ter)), splice-site, frameshift, and deleterious missense changes. Recurrent regional alleles such as p.Gln564Ter illustrate founder effects in Central Europe. Reported: c.1690C>T (p.Gln564Ter).

Functional studies establish BARD1 as a critical partner of BRCA1 in homology-directed repair (HDR) and ubiquitin ligase activity. The BRCA1/BARD1 heterodimer assembles non-Lys48 polyubiquitin chains and binds RAD51, promoting DNA damage–induced nuclear foci (PMID:11278247). HDR assays of 29 BARD1 missense variants showed that pathogenic substitutions in the RING and ankyrin domains abrogate repair activity (PMID:26350354).

Contradictory evidence arises from meta-analyses of common polymorphisms: the Cys557Ser variant showed no significant risk in 11 870 cases vs. 7 687 controls (OR 1.14) (PMID:21809034), and small familial cohorts in Australia failed to support BARD1 as a high-penetrance gene (PMID:17972171).

Overall, genetic and functional data support a moderate ClinGen clinical validity for BARD1–breast cancer association, reinforced by subtype specificity and mechanistic concordance. Genetic testing panels including BARD1 can guide risk stratification and management in patients with familial or triple-negative breast cancer.

References

• Cell • 2001 • The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression PMID:11257228
• The Journal of biological chemistry • 2001 • The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation PMID:11278247
• JAMA Oncology • 2017 • Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer PMID:28418444
• Cancers • 2019 • BARD1 is A Low/Moderate Breast Cancer Risk Gene: Evidence Based on An Association Study of the Central European p.Q564X Recurrent Mutation PMID:31142030
• Human Mutation • 2015 • Functional Analysis of BARD1 Missense Variants in Homology-Directed Repair of DNA Double Strand Breaks PMID:26350354
• Journal of the National Cancer Institute • 2020 • The Contribution of Germline Predisposition Gene Mutations to Clinical Subtypes of Invasive Breast Cancer From a Clinical Genetic Testing Cohort PMID:32091585
• Journal of Cancer Research and Clinical Oncology • 2011 • Lack of association between BARD1 Cys557Ser variant and breast cancer risk: a meta-analysis of 11,870 cases and 7,687 controls PMID:21809034
• Breast Cancer Research and Treatment • 2008 • BARD1 variants are not associated with breast cancer risk in Australian familial breast cancer PMID:17972171

Evidence Based Scoring (AI generated)