rs752514155
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2
The NM_000465.4(BARD1):c.55G>T(p.Glu19Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 1,597,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E19E) has been classified as Likely benign.
Frequency
Consequence
NM_000465.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.55G>T | p.Glu19Ter | stop_gained | 1/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.55G>T | p.Glu19Ter | stop_gained | 1/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000278 AC: 6AN: 215878Hom.: 0 AF XY: 0.0000167 AC XY: 2AN XY: 119556
GnomAD4 exome AF: 0.00000692 AC: 10AN: 1445022Hom.: 0 Cov.: 74 AF XY: 0.00000279 AC XY: 2AN XY: 717954
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2019 | Variant summary: BARD1 c.55G>T (p.Glu19X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 215878 control chromosomes. To our knowledge, no occurrence of c.55G>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with other pathogenic variant has been reported (BRCA1 c.45delT, p.Asn16MetfsX7) at our laboratory. Six clinical diagnostic laboratories (Pathogenic n=5; VUS n=1) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 17, 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 | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Glu19*) 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 (rs752514155, gnomAD 0.02%). 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: 233594). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 24, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 02, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2015 | This pathogenic variant is denoted BARD1 c.55G>T at the cDNA level and p.Glu19Ter (E19X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The p.E19* pathogenic mutation (also known as c.55G>T), located in coding exon 1 of the BARD1 gene, results from a G to T substitution at nucleotide position 55. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. 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 | Jun 03, 2021 | This variant changes 1 nucleotide in exon 1 of the BARD1 gene, creating a 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 7/247256 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at