chr17-61683395-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_032043.3(BRIP1):c.3651G>A(p.Trp1217Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,158 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 stop_gained
NM_032043.3 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 0.0280
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 2 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. Fraction of 0.0264 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.3651G>A | p.Trp1217Ter | stop_gained | 20/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.3651G>A | p.Trp1217Ter | stop_gained | 20/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152110Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250810Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135566
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461048Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 726784
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152110Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 29, 2022 | Variant summary: BRIP1 c.3651G>A (p.Trp1217X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the last 33 amino acids of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory. The variant allele was found at a frequency of 1.9e-05 in 261294 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3651G>A has been reported in the literature as a germline VUS variant in cases of men with aggressive prostate cancer undergoing multigene panel testing (example, Nguyen-Dumont_2021), in settings of multigene panel testing in a case of chronic eosinophlic leukemia with novel t(5;12) (q23;31;p13)/ETV6-ACSL6 gene fusion, in which patient was resistant to TKI therapy (example, Su_2016), in a glioblastoma tumor type within The Cancer Genome Atlas (TGCA) collection (example, Lu_2015), in control cohorts from the ExAC database (example, Weber-Lassalle_2018), and an other UK control cohort (example, Easton_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 09, 2023 | The p.W1217* variant (also known as c.3651G>A) located in coding exon 19 of the BRIP1 gene, results from a G to A substitution at nucleotide position 3651. This changes the amino acid from a tryptophan to a stop codon within coding exon 19. In one case-control study, this alteration was identified in 0/13213 breast cancer cases and in 1/5242 controls from the United Kingdom (Easton DF et al. J. Med. Genet. 2016 May;53:298-309). 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 removes only the last 33 amino acids of the protein. The exact functional impact of these removed 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 Ju;8:e1002786). Since supporting evidence is conflicting 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 | Jul 28, 2020 | This variant changes 1 nucleotide in exon 20 of the BRIP1 gene, creating a premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282186 chromosomes 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 | Oct 26, 2022 | This sequence change creates a premature translational stop signal (p.Trp1217*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs542698396, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186726). 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. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2017 | This variant is denoted BRIP1 c.3651G>A at the cDNA level and p.Trp1217Ter (W1217X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA). This variant has not, to our knowledge, been reported in the literature as a germline pathogenic or benign variant. Due to the position of the variant, nonsense mediated decay is not expected to occur, but it might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene is not within any known functional domain. BRIP1 Trp1217Ter was observed at an allele frequency of 0.01% (1/10302) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on currently available information, we consider RAD51D Gln319Ter to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
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Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at