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

dbSNP: rs750413473

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213123	SCV000274099	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-18	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476131	SCV000545582	likely pathogenic	Familial cancer of breast	2024-12-29	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, 36551643). 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	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000476131	SCV004217270	likely pathogenic	Familial cancer of breast	2024-03-09	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.