ClinVar Genomic variation as it relates to human health

This variant inserts 1 nucleotide in exon 11 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/251318 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

This sequence change creates a premature translational stop signal (p.Asn744*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the BARD1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 460740). This variant disrupts the C-terminal BRCT domain of BARD1 protein, which is required for chromosome stability and homology-directed repair (PMID: 17848578). A different variant (p.Val767fs) that lies downstream of this variant has been reported to affect BARD1 protein function (PMID: 30925164), this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The c.2229dupT variant, located in coding exon 11 of the BARD1 gene, results from a duplication of T at nucleotide position 2229, causing a translational frameshift with a predicted alternate stop codon (p.N744*). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of BARD1, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 34 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Another truncating alteration downstream, p.V767fs*4 (c.2300_2301delTG), was found to be non-functional in a homology-directed DNA repair through functional studies (Adamovich AI et al. PLoS Genet. 2019 03;15:e1008049). One study detected the p.N744* alteration in 0/3030 pancreatic cancer cases and 1/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This alteration was also identified in one Hispanic individual undergoing genetic assessment at a hereditary breast and ovarian cancer center (Chapman-Davis E et al. J Gen Intern Med, 2021 01;36:35-42).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.