ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
20077502 Brakeleer et al (2010) Mutation analysis of the entire coding region of BARD1 as well as the intron-exon boundaries . Study consisted of 196 high risk breast and/or ovarian cancer families, which included 151 "breast cancer only" and 45 that also included ovarian cancer. All high risk families were negative for BRCA1/2 alterations. Female patient diagnosed with breast cancer at 68, identified frameshift alteration (c.1935_1954dup, p.Glu652ValfsX69) originated from a duplication of twenty nucleotides in exon 10, creating a premature stop codon, predicted to result in the loss of the entire second functional BRCT domain. Co-segregation analysis showed the same alteration present in two affected sisters (breast cancer, diagnosed at ages 42 and 38) and NOT present in any unaffected family members tested (proband's brother and two daughters). Nonsense mediated decay was not observed in leukocytes from mutation carriers, suggesting truncated BARD1 protein might accumulate in breast epithelial cells.
20842729 Sabatier et al (2010) Single 36 year old female with basal breast cancer and a family history of breast cancer (mother, diagnosed at age 51), who tested negative for BRCA1/2 alterations. Tumor profiling using aCGH identified a somatic homozygous deletion of BARD1; confirmed germline heterozygous deletion. Tumor displayed a BRCA1-inactivation profile/BRCA1-mutated-like profile (both suggestive of a BRCA1-deficiency). Mother was unavailable for testing.
21344236; 25994375 Ratajska et al (2012) and Klonowska et al (2015) Two studies looking at Polish patients from families with breast (Br) and/or ovarian (Ov) cancer (109 and 817 patients, respectively) using DHPLC/bi-directional sequencing or MLPA/sequencing, respectively. Ratajska patients were negative for BRCA1/2 alterations, and Klonowska patients were BRCA negative for the the five most common BRCA1 alterations in the Polish population that accounts for >90% of all BRCA mutations. Ratajaska et al identified three novel BARD1 variants (c.1312-2A>G, c.1690C>T, c.1977A>G) that were absent/low frequency in controls. The first variant (c.1312-2A>G) was identified in proband (Br, 40), proband's affected mother (Br, 50), and proband's unaffected son (age unknown). The second variant (c.1690C>T, p.Gln564*) identified in proband (Br, 46) and proband's affected mother (Br, 75); same variant also identified by Klonowska et al in two additional families (Br/Ov and Br). The third variant (c.1977A>G, p.Arg659Arg; apparently silent alteration that affects several exonic splicing enhancer motifs, resulting in the deletion of exons 2-9, leading to a frameshift and the premature termination of translation, p.Cys53_Trp635delinsfs*12) identified in proband (Ov, 36) and affected maternal grandma (Br, 52) and affected maternal great aunt (genital tract ca, unknown); same variant also identified by Klonowska et al in three additional families (Br/Ov, Br/Ov, and Br).

Haploinsufficiency phenotype comments:

Haploinsufficiency/loss of function variants are presumed to result in increased risk for breast cancer.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

no evidence for triplosensitivity