rs786203056
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000465.4(BARD1):c.539_540del(p.Tyr180Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y180Y) 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.539_540del | p.Tyr180Ter | frameshift_variant | 4/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.539_540del | p.Tyr180Ter | frameshift_variant | 4/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250646Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135448
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461076Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 726696
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change creates a premature translational stop signal (p.Tyr180*) 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). This variant is present in population databases (rs779427628, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 186576). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 19, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | This sequence change creates a premature translational stop signal (p.Tyr180*) 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). This variant is present in population databases (rs779427628, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 186576) with 4 submissions. Therefore, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The c.539_540delAT pathogenic mutation, located in coding exon 4 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 539 to 540, causing a translational frameshift with a predicted alternate stop codon (p.Y180*). This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119) and was seen in 0/3030 cases of pancreatic cancer and 1/123136 controls from gnomAD (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. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 2 nucleotides in exon 4 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. This variant has been identified in 3/282036 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28724667) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at