ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.2063dup (p.Asp689fs)

dbSNP: rs1064796026
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481853 SCV000572392 likely pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing This duplication of one nucleotide in BARD1 is denoted c.2063dupA at the cDNA level and p.Asp689GlyfsX5 (D689GfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CCAA[dupA}GGAC. The duplication causes a frameshift which changes an Aspartic Acid to a Glycine at codon 689, and creates a premature stop codon at position 5 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 89 amino acids are no longer translated. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Ambry Genetics RCV000564064 SCV000665756 pathogenic Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing The c.2063dupA pathogenic mutation, located in coding exon 11 of the BARD1 gene, results from a duplication of A at nucleotide position 2063, causing a translational frameshift with a predicted alternate stop codon (p.D689Gfs*5). The stop codon occurs in the last exon of the gene, so while it is truncating, the mRNA may escape nonsense mediated decay (NMD). Premature termination codons located either in the last exon or within 50-55 nucleotides upstream of the 3'-most exon-exon junction usually fail to elicit NMD (Maquat LE et al. Nat. Rev. Mol. Cell Biol. 2004 Feb; 5(2):89-99). However, the c.2063dupA alteration is located 5' to the BARD1 BRCT protein domain, which has been described as similar to those of the BRCA1 gene, and may be important for ligand binding (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12). Further, an additional pathogenic mutation in the BARD1 gene, c.2148_2149delCA, is located 3’ to this alteration and has been described in a patient diagnosed with fallopian tube cancer at age 53 (Walsh, T el al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7). Based on the available evidence, c.2063dupA is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV000564064 SCV001350141 pathogenic Hereditary cancer-predisposing syndrome 2020-01-24 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 11 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31386 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 Pathogenic.
Invitae RCV001208591 SCV001379987 likely pathogenic Familial cancer of breast 2023-10-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp689Glyfs*5) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the BARD1 protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 422826). 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.
Myriad Genetics, Inc. RCV001208591 SCV004045102 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001208591 SCV004171490 likely pathogenic Familial cancer of breast 2023-10-18 criteria provided, single submitter clinical testing The BARD1 c.2063dup (p.Asp689GlyfsTer5) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This variant is not expected to result in nonsense-mediated decay, but it is predicted to disrupt the c-terminal BRCT domain required for chromosome stability and homology-directed repair (PMID: 17848578). This variant has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). To our knowledge, this variant has not been reported in individuals with BARD1-associated diseases; however, downstream loss of function variants have been reported (PMID: 30925164; ClinVar ID: 820952, 863791). This variant is absent in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic.
Baylor Genetics RCV001208591 SCV004217309 likely pathogenic Familial cancer of breast 2022-12-19 criteria provided, single submitter clinical testing

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