rs767395666
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_000465.4(BARD1):c.2203C>T(p.Gln735Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q735Q) 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 Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.2203C>T | p.Gln735Ter | stop_gained | 11/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.2203C>T | p.Gln735Ter | stop_gained | 11/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251334Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135822
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change creates a premature translational stop signal (p.Gln735*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the BARD1 protein. This variant is present in population databases (rs767395666, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28486781, 29752822). This variant is also known as c.2257C>T. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at