rs587780236
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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.2273dupT(p.Ala759fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 frameshift
NM_032043.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.58
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-61743118-T-TA is Pathogenic according to our data. Variant chr17-61743118-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2273dupT | p.Ala759fs | frameshift_variant | 16/20 | ENST00000259008.7 | NP_114432.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2273dupT | p.Ala759fs | frameshift_variant | 16/20 | 1 | NM_032043.3 | ENSP00000259008.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251216Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135768
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727150
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Mar 06, 2024 | ACMG Criteria: PVS1, PM2, PP4, PP5; Variant was found in heterozygous state - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 02, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 08, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2019 | Variant summary: BRIP1 c.2273dupT (p.Ala759SerfsX6) results in a premature termination codon, predicted to cause a truncation 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 been classified as pathogenic by our laboratory (c.2392C>T, p.Arg798X; c.2400C>G, p.Tyr800X). The variant allele was found at a frequency of 8e-06 in 251216 control chromosomes (gnomAD). c.2273dupT has been reported in the literature in individuals affected with endometrial, prostate, ovarian or breast cancer (Susswein_2016, Pritchard_2016, Weber-Lassalle_2018). These data indicate that the variant is likely to be associated with disease. 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2018 | - - |
Likely pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Dec 04, 2019 | Curator: Arleen D. Auerbach. Submitter to LOVD: Andreas Laner. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2024 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 29922827, 27433846, 27806231, 29368626, 29625052, 32359370, 36451132, 33471991) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 28, 2024 | The c.2273dupT pathogenic mutation, located in coding exon 15 of the BRIP1 gene, results from a duplication of T at nucleotide position 2273, causing a translational frameshift with a predicted alternate stop codon (p.A759Sfs*6). This alteration has been identified in individuals diagnosed with breast, ovarian and/or prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; Weber-Lassalle N et al. Breast Cancer Res, 2018 01;20:7; Dorling et al. N Engl J Med. 2021 02;384:428-43) and in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant inserts 1 nucleotide in exon 16 of the BRIP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 2/251216 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 Pathogenic. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Ala759Serfs*6) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs587780236, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 26681312, 27433846, 29368626). ClinVar contains an entry for this variant (Variation ID: 128170). For these reasons, this variant has been classified as Pathogenic. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 18, 2016 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at