Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164774 | SCV000215450 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-03-23 | criteria provided, single submitter | clinical testing | The p.W756* variant (also known as c.2268G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide position 2268. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. 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 22 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests this alteration results in loss of a large part of a well-ordered C-terminal BRCT domain with destabilization of the structure, 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV003500508 | SCV004293074 | likely pathogenic | Familial cancer of breast | 2023-08-31 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp756*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the BARD1 protein. This variant is not present in population databases (gnomAD no frequency). 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: 185366). 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. |