ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.2300_2301del (p.Val767fs)

dbSNP: rs750413473
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213123 SCV000274099 likely pathogenic Hereditary cancer-predisposing syndrome 2022-11-17 criteria provided, single submitter clinical testing The c.2300_2301delTG variant, located in coding exon 11 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 2300 to 2301, causing a translational frameshift with a predicted alternate stop codon (p.V767Dfs*4). This alteration occurs at the 3' terminus of BARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last eleven amino acids of the protein. However, premature stop codons are typically deleterious in nature and structural analysis suggests this alteration would destabilize one of the BRCT domains in the BARD1 protein which are important for interactions with several proteins (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). This alteration was found to be non-functional in a homology-directed DNA repair (Adamovich AI et al. PLoS Genet. 2019 03;15:e1008049). This variant has been detected in at least two individuals with triple-negative breast cancer and one individual with serous ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb; 33(4):304-11; Gong Y et al. Int J Mol Sci. 2021 Aug;22:; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11)). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000308990 SCV000329104 likely pathogenic not provided 2023-05-12 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation as the last 11 amino acids are lost and replaced with 3 incorrect amino acids in the critical BRCT 2 domain; Published functional studies suggest a damaging effect: reduced HDR activity (Adamovich et al., 2019); Observed in individuals with breast, ovarian, and other cancers (Couch et al., 2015; Ramus et al., 2015; Gong et al., 2021; Truong et al., 2021; El Jabbour et al., 2022; Nurmi et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25452441, 14578343, 26315354, 18842000, 17550235, 15782130, 29922827, 32075053, Imyanitov[case report], 30925164, 17848578, 34445631, 35078243, 36551643, 34654685)
Invitae RCV000476131 SCV000545582 likely pathogenic Familial cancer of breast 2023-12-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val767Aspfs*4) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the BARD1 protein. This variant is present in population databases (rs750413473, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 25452441, 26315354). ClinVar contains an entry for this variant (Variation ID: 230523). 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.
Counsyl RCV000476131 SCV000785728 pathogenic Familial cancer of breast 2017-11-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000213123 SCV000903025 likely pathogenic Hereditary cancer-predisposing syndrome 2023-01-09 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides in exon 11 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is not expected to trigger nonsense-mediated decay. This variant is predicted to delete or alter the last 11 amino acids of the BARD1 protein, including the C-terminus of the BRCT2 domain that facilitates protein-protein interaction involved in BARD1's role in DNA repair and tumor suppression (PMID: 17550235, 17848578, 26738429). A functional study has found the variant protein to be severely compromised for homology-directed repair activity in human cell assays (PMID: 30925164). This variant has been reported in three individuals affected with breast cancer, including two individuals with triple-negative breast cancer (PMID: 25452441, 34445631, 36551643). This variant has also been reported in an individual with ovarian cancer (PMID: 26315354) and in an individual over the age of 70 without cancer (FLOSSIES database). This variant has been identified in 9/282570 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.
Sema4, Sema4 RCV000213123 SCV002529599 likely pathogenic Hereditary cancer-predisposing syndrome 2021-09-19 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000476131 SCV004019255 pathogenic Familial cancer of breast 2023-02-24 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000308990 SCV004024833 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000476131 SCV004217270 likely pathogenic Familial cancer of breast 2023-05-15 criteria provided, single submitter clinical testing
CZECANCA consortium RCV001270958 SCV001451762 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000476131 SCV002589057 pathogenic Familial cancer of breast 2022-08-26 no assertion criteria provided clinical testing
Diagnostics Centre, Carl Von Ossietzky University Oldenburg RCV000476131 SCV004174180 pathogenic Familial cancer of breast 2023-08-22 no assertion criteria provided clinical testing The variant BARD1:c.2300_2301delTG, p.(Val767Aspfs*4), which is located in the coding exon 11 of the BARD1 gene, results from a deletion of nucleotide positions 2300 and 2301. This leads to a frameshift and a premature stop codon after four amino acids which is predicted to cause protein truncation. The variant affects the BRCT2 domain, which plays a crucial role in the protein function associated to in DNA repair and tumor suppression. The variant is described four times as pathogenic and five times as probably pathogenic in Clinvar (Clinvar ID: 230523). The varinat has been detected in individuals affected with breast cancer (PMID: 34445631, 32075053, 25452441) and ovarian carcinoma (PMID: 26315354). In a functional study, a loss of function of the truncated BARD1 gene product in relation to homology-directed repair was demonstrated based on a cell culture assay (PMID: 30925164). The variant is very rare, with an allele frequency in the overall population= 0.00001 (gnomAD V3.1.2). The variant is classified as Pathogenic.

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