ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.2229dup (p.Asn744Ter) (rs1259296823)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000531970 SCV000633021 likely pathogenic Familial cancer of breast 2020-03-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BARD1 gene (p.Asn744*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 34 amino acids of the BARD1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BARD1-related disease. ClinVar contains an entry for this variant (Variation ID: 460740). This variant disrupts part of 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.
Ambry Genetics RCV001014816 SCV001175575 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing 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. The exact functional impact of these removed amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV001014816 SCV001351400 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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