rs1295703239
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_032043.3(BRIP1):c.2786_2789del(p.Leu929HisfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,176 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. L929L) has been classified as Likely benign.
Frequency
Consequence
NM_032043.3 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2786_2789del | p.Leu929HisfsTer55 | frameshift_variant | 19/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2786_2789del | p.Leu929HisfsTer55 | frameshift_variant | 19/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 21, 2019 | - - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Dec 23, 2019 | Curator: Arleen D. Auerbach. Submitter to LOVD: Florentia Fostira. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change creates a premature translational stop signal (p.Leu929Hisfs*55) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 321 amino acid(s) of the BRIP1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 31300551). ClinVar contains an entry for this variant (Variation ID: 530300). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Lys998Glufs*6) have been determined to be pathogenic (PMID: 18628483, 26921362, 28423363; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 16, 2020 | This variant deletes 4 nucleotides in exon 19 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). Although functional studies have not been reported for this variant, this variant is expected to impair important BRIP1 protein function. This variant has been reported in an individual affected with breast cancer (PMID: 31300551). This variant has been identified in 1/250646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 07, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at