rs786203717
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_032043.3(BRIP1):βc.2992_2995delβ(p.Lys998GlufsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. K998K) has been classified as Likely benign.
Frequency
Consequence
NM_032043.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2992_2995del | p.Lys998GlufsTer60 | frameshift_variant | 20/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2992_2995del | p.Lys998GlufsTer60 | frameshift_variant | 20/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251076Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135696
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461590Hom.: 0 AF XY: 0.0000206 AC XY: 15AN XY: 727098
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74316
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 28, 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 | MGZ Medical Genetics Center | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 26, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 03, 2023 | Criteria applied: PVS1,PS3,PS4,PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Dec 11, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 17, 2021 | - - |
Uncertain significance, flagged submission | research | Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2024 | The c.2992_2995delAAGA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides between positions 2992 and 2995, causing a translational frameshift with a predicted alternate stop codon. This mutation has been identified in early onset breast cancer and ovarian cancer patients (De Nicolo A et al. Clin. Cancer Res. 2008 Jul; 14(14):4672-80; Tedaldi G et al. Oncotarget 2017 Jul;8(29):47064-47075; Carter NJ et al. Gynecol Oncol. 2018 Dec;151(3):481-488). Functional analysis indicates that the premature truncation resulting from this alteration interferes with the stability of the protein and with its ability to interact with BRCA1 (De Nicolo A et al. Clin. Cancer Res. 2008 Jul; 14(14):4672-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 06, 2022 | This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). A functional study has shown that this variant affects protein stability and impairs interaction with BRCA1 (PMID: 18628483). This variant has been reported in multiple individuals affected with breast cancer or from a high risk family (PMID: 18628483, 26921362, 28423363, 29368626, 31325073). One of these individuals also carried a pathogenic variant in the BRCA2 gene (PMID: 28423363). This variant has been observed in multiple individuals affected with breast cancer or having a family history of breast, ovarian or colorectal cancer (Color internal data). This variant has been identified in 5/282468 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 Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 20, 2019 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | BRIP1: PVS1:Strong, PM2, PS3:Moderate, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 12, 2023 | This frameshift variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. The frequency of this variant in the general population, 0.000023 (3/129046 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast and/or ovarian cancer (PMID: 18628483 (2008), 26921362 (2016), 28423363 (2017), 29368626 (2018), 30322717 (2018), and 31325073 (2019)), as well as in an individual with acute myeloid leukemia (PMID: 33840814 (2021)). One functional study on transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1 (PMID: 18628483 (2008)), while another demonstrated reduced protein expression and BRCA1 binding disruption (PMID: 21345144 (2011)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 252 amino acids are lost and replaced with 59 incorrect amino acids; Published functional studies demonstrate a damaging effect: impaired protein stability and interaction with BRCA1 (De Nicolo et al., 2008); Observed in individuals with breast, ovarian, or renal cancer (De Nicolo et al., 2008; Easton et al., 2016; Tedaldi et al., 2017; Carter et al., 2018; Yngvadottir et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21345144, 26921362, 20159562, 18628483, 20346647, 29368626, 31325073, 34426522, 35441217, 29922827, 33840814, 28423363, 30322717) - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Lys998Glufs*60) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 252 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs786203717, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18628483, 26921362, 28423363). ClinVar contains an entry for this variant (Variation ID: 187416). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRIP1 function (PMID: 18628483, 20159562, 21127055, 21345144). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Ser1070Glnfs*8) 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. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 13, 2018 | - - |
Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 10, 2019 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2022 | Variant summary: BRIP1 c.2992_2995delAAGA (p.Lys998GlufsX60) results in a premature termination codon causes a truncation of the encoded protein which is a commonly known mechanism for disease (De Nicolo_2008). Truncations downstream of this position have been observed at our laboratory and reported in association with other BRIP1-related cancers in the HGMD database. The variant allele was found at a frequency of 1.6e-05 in 251076 control chromosomes. c.2992_2995delAAGA has been reported in the literature among individuals with a variety of BRIP1-associated cancers such as breast/ovarian and AML (example, De Nicolo_2008, Tedaldi_2017, Carter_2018, Weber-Lassalle_2018, Wagener_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Di Nicolo_2008). The most pronounced variant effect impairs BRIP1 function and its ability to interact with BRCA1. Eight 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. - |
Breast carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at