Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000635702 | SCV000757123 | likely pathogenic | Familial cancer of breast | 2017-10-11 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the BARD1 gene (p.Trp680Asnfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acids of the BARD1 protein. This variant is not present in population databases (ExAC no frequency). 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. This truncating change removes most of the BRCT2 domain of BARD1 (residues 666-777) (PMID: 26315354, 17550235). While the functional significance of deleting the second BRCT domain has not been addressed experimentally, studies suggest that both BRCT repeats in BARD1 are necessary for its normal functioning (PMID: 17550235, 26738429, 17848578). This variant has not been reported in the literature in individuals with BARD1-related disease. |
| Ambry Genetics | RCV002420706 | SCV002720253 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-08-19 | criteria provided, single submitter | clinical testing | The c.2038_2042delTGGGG variant, located in coding exon 11 of the BARD1 gene, results from a deletion of 5 nucleotides at nucleotide positions 2038 to 2042, causing a translational frameshift with a predicted alternate stop codon (p.W680Nfs*12). This alteration occurs at the 3' terminus of theBARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 87 amino acids of the protein. However, structural analysis suggests this alteration results in loss of a large part of a well-ordered C-terminal BRCT domain, which could disrupt protein-protein interactions (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12; Feki A et al. Oncogene 2005 May; 24(23):3726-36; Edwards RA et al. Biochemistry 2008 Nov; 47(44):11446-56; Rodriguez M et al. J. Biol. Chem. 2003 Dec; 278(52):52914-8; Ambry internal data). In addition, the BARD1 C-terminal BRCT domain has been implicated in chromosomal stability and homology-directed repair function (Laufer M et al. J. Biol. Chem., 2007 Nov;282:34325-33). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Myriad Genetics, |
RCV000635702 | SCV004044431 | pathogenic | Familial cancer of breast | 2023-05-25 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |