rs1491231712
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_032043.3(BRIP1):c.3730_3731insAGGCA(p.Met1244LysfsTer12) 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 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Consequence
BRIP1
NM_032043.3 frameshift
NM_032043.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.528
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1263 codons.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.3730_3731insAGGCA | p.Met1244LysfsTer12 | frameshift_variant | 20/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.3730_3731insAGGCA | p.Met1244LysfsTer12 | frameshift_variant | 20/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33
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GnomAD4 exome Cov.: 31
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2023 | The c.3726_3730dupAGGCA variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of AGGCA at nucleotide position 3726, causing a translational frameshift with a predicted alternate stop codon (p.M1244Kfs*12). This alteration occurs at the 3' terminus of BRIP1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 6 amino acids. This frameshift impacts the last 6 amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 11, 2019 | This variant inserts 5 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift in the last coding exon and addition of 6 new amino acids before introducing a stop codon. This mutant transcript is predicted to escape nonsense-mediated decay. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been reported in 1 individual age 70 years or older without cancer by FLOSSIES (https://whi.color.com/variant/17-59760676--TGCCT). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. RNA analysis performed to evaluate the impact of this frameshift on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 407814). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the BRIP1 gene (p.Met1244Lysfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the BRIP1 protein and extend the protein by 5 additional amino acid residues. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 03, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at