rs1553622558
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000465.4(BARD1):c.624dupG(p.Lys209GlufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). 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
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
The c.624dupG pathogenic mutation, located in coding exon 4 of the BARD1 gene, results from a duplication of G at nucleotide position 624, causing a translational frameshift with a predicted alternate stop codon (p.K209Efs*5). 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. -
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This variant inserts 1 nucleotide 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 reported in an individual affected with breast cancer with family history of ovarian cancer (PMID: 31036035). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different nucleotide change that results into the same protein consequence (c.623dupA, p.Lys209Glufs*5) is known to be disease-causing (ClinVar variation ID: 127742). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Familial cancer of breast Pathogenic:3
This sequence change creates a premature translational stop signal (p.Lys209Glufs*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). 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: 482768). For these reasons, this variant has been classified as Pathogenic. -
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at