Submissions for variant NM_000465.4(BARD1):c.2129_2132del (p.Asp710fs)

dbSNP: rs1692216921

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001051179	SCV001215321	likely pathogenic	Familial cancer of breast	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp710Valfs*3) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 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: 847596). 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.
Ambry Genetics	RCV002416385	SCV002726106	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-25	criteria provided, single submitter	clinical testing	The c.2129_2132delACAG variant, located in coding exon 11 of the BARD1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2129 to 2132, causing a translational frameshift with a predicted alternate stop codon (p.D710Vfs*3). This alteration occurs at the 3' terminus of theBARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 67 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). In addition, this alteration impacts the BRCT domain of BARD1, which has been shown to be necessary for homology-directed DNA repair (Laufer M et al. J Biol Chem. 2007 Nov;282:34325-33, Adamovich AI et al. PLoS Genet. 2019 03;15:e1008049). This alteration has been reported in one individual diagnosed with breast cancer at age 42 and with familial history of breast and ovarian cancer (Rofes P et al. Genes (Basel). 2021 Jan;12:). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV001051179	SCV004044341	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.
Revvity Omics, Revvity	RCV003490033	SCV004238494	likely pathogenic	not provided	2021-09-06	criteria provided, single submitter	clinical testing