rs786201868
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000465.4(BARD1):c.860_861del(p.Glu287ValfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E287E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000465.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.860_861del | p.Glu287ValfsTer5 | frameshift_variant | 4/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.860_861del | p.Glu287ValfsTer5 | frameshift_variant | 4/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249484Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134862
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460480Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726358
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 185015). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is present in population databases (rs786201868, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Glu287Valfs*5) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jan 06, 2022 | This variant has been previously reported as disease causing in PMID: 28152038. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 19, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The c.860_861delAG pathogenic mutation, located in coding exon 4 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 860 to 861, causing a translational frameshift with a predicted alternate stop codon (p.E287Vfs*5). This mutation has been detected in a cohort of patients who underwent multi-gene panel testing (LaDuca H et al. PLoS ONE. 2017 Feb;12:e0170843). This alteration was not detected in a cohort of 3030 pancreatic cancer patients undergoing multi-gene panel testing, but was identified in 1/123,136 gnomAD controls (Hu C et al. JAMA. 2018 06;319:2401-2409). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at