rs763443434
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_032043.3(BRIP1):c.3004_3005insTGACAGCT(p.Trp1002LeufsTer60) 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 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 frameshift
NM_032043.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.07
Genes affected
BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-61684041-C-CAGCTGTCA is Pathogenic according to our data. Variant chr17-61684041-C-CAGCTGTCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.3004_3005insTGACAGCT | p.Trp1002LeufsTer60 | frameshift_variant | 20/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.3004_3005insTGACAGCT | p.Trp1002LeufsTer60 | frameshift_variant | 20/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251210Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135750
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461616Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727100
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:2
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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 12, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2022 | This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Asn1006*) have been determined to be pathogenic (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. ClinVar contains an entry for this variant (Variation ID: 186335). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is present in population databases (rs763443434, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Trp1002Leufs*60) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 248 amino acid(s) of the BRIP1 protein. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 27, 2017 | This frameshift variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. The variant has not been reported in the published literature. However, a different, but related frameshift variant was identified in a family affected with breast cancer and it was shown to be unstable (PMID: 18628483 (2008)). The frequency of the c.3004_3005insTGACAGCT variant in the general population, 0.0000071 (2/282596 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 04, 2021 | The c.3004_3005insTGACAGCT pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from an insertion of 8 nucleotides at position 3004, causing a translational frameshift with a predicted alternate stop codon (p.W1002Lfs*60). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 248 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell, 2010 Feb;37:438-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at