rs777367075
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_032043.3(BRIP1):c.3525dupT(p.Ile1176TyrfsTer13) 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 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032043.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250646Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135542
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461226Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726918
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74388
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
This variant inserts 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein. This variant would disrupt acetylation at the Lys1249 residue of the BRIP1 protein, which is reported to be important for the DNA repair response (PMID: 22792074). However, the role of this post-translational modification in disease is not clearly understood. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26921362; Color internal data) and thyroid papillary cancer (PMID: 29625052). This variant has been identified in 3/282052 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
The c.3525dupT variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of T at nucleotide position 3525, causing a translational frameshift with a predicted alternate stop codon (p.I1176Yfs*13). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 74 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). The exact functional impact of these altered amino acids is unknown at this time; however, structural and functional studies suggest that at least two residues contained in this deleted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal. 2010 Jan;3:ra3; Xie J et al. PLoS Genet. 2012 Jul;8:e1002786). This alteration has been previously identified in 1 of 13213 breast cancer cases and 0 of 5242 controls (Easton DF et al. J. Med. Genet. 2016 05;53:298-309). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:2
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This sequence change creates a premature translational stop signal (p.Ile1176Tyrfs*13) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 74 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs777367075, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with breast cancer and/or thyroid carcinoma (PMID: 26921362, 29625052). ClinVar contains an entry for this variant (Variation ID: 216799). 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. -
not provided Uncertain:1
This duplication of one nucleotide in BRIP1 is denoted c.3525dupT at the cDNA level and p.Ile1176TyrfsX13 (I1176YfsX13) at the protein level. The normal sequence, with the base that is duplicated in braces, is GAAC[T]ATAA. The duplication causes a frameshift which changes an Isoleucine to a Tyrosine at codon 1176 in the last exon of the protein, exon 20, and creates a premature stop codon at position 13 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause protein truncation. The last 74 amino acids of the protein are replaced by 12 incorrect amino acids, the clinical significance of which is unclear. The lost region is moderately conserved across species and is not within any known functional domain. This variant was not observed in approximately 6,500 individuals of European and African ancestry the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available information, it is unclear whether this duplication is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at