ClinVar Genomic variation as it relates to human health
NM_032043.3(BRIP1):c.2992_2995del (p.Lys998fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(14); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_032043.3(BRIP1):c.2992_2995del (p.Lys998fs)
Variation ID: 187416 Accession: VCV000187416.33
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 17q23.2 17: 61684051-61684054 (GRCh38) [ NCBI UCSC ] 17: 59761412-59761415 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 May 1, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032043.3:c.2992_2995del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_114432.2:p.Lys998fs frameshift NM_032043.2:c.2992_2995delAAGA NC_000017.11:g.61684052_61684055del NC_000017.10:g.59761413_59761416del NG_007409.2:g.184506_184509del LRG_300:g.184506_184509del LRG_300t1:c.2992_2995del LRG_300p1:p.Lys998fs - Protein change
- K998fs
- Other names
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- Canonical SPDI
- NC_000017.11:61684050:TCTTT:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BRIP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5542 | 5596 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 6, 2022 | RCV000167141.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV000458808.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 8, 2023 | RCV000478533.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 13, 2018 | RCV000663176.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 10, 2019 | RCV001781517.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002265649.1 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 9, 2021 | RCV001554295.2 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2023 | RCV002288764.6 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547613.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579452.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS3, PM2_SUP
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Nov 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004175999.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
Criteria applied: PVS1,PS3,PS4,PM2_SUP
Clinical Features:
Family history of cancer (present)
Sex: female
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Pathogenic
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004214739.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017944.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Mar 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684241.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: no
Allele origin:
unknown
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Genomic Medicine Lab, University of California San Francisco
Accession: SCV004847121.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
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Pathogenic
(May 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000217971.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Apr 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Neoplasm of ovary
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786341.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Pathogenic
(Mar 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448750.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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criteria provided, single submitter
Method: research
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
paternal
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Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf
Accession: SCV001482294.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Family history: no
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Pathogenic
(Mar 17, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002533667.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRIP1 c.2992_2995delAAGA (p.K998EfsX60) variant has been reported in heterozygosity in several individuals with breast or ovarian cancer, often diagnosed under age 50 (PMID: 18628483, … (more)
The BRIP1 c.2992_2995delAAGA (p.K998EfsX60) variant has been reported in heterozygosity in several individuals with breast or ovarian cancer, often diagnosed under age 50 (PMID: 18628483, 28423363, 29368626, 26921362, 31325073, 30322717). Functional studies have shown that this variant alters the BRCA1-binding domain, thereby impairing the interaction of BRIP1 with BRCA1 (PMID: 18628483). As this variant is not predicted to cause nonsense-mediated decay, the protein product is expected to be truncated. It has been shown that this truncated BRIP1 protein is unstable and is degraded more quickly than the wildtype protein (PMID: 18628483). This variant was observed in 1/24956 chromosomes in the African/African American population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 187416). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000564817.6
First in ClinVar: Apr 27, 2017 Last updated: May 20, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Feb 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019355.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Apr 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220715.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Fanconi anemia complementation group J
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000547323.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Aug 09, 2021)
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no assertion criteria provided
Method: clinical testing
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Breast carcinoma
Affected status: yes
Allele origin:
germline
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Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001774870.1
First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021 |
Age: 20-29 years
Sex: female
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer. | Wagener R | European journal of human genetics : EJHG | 2021 | PMID: 33840814 |
Assessing the effectiveness of the National Comprehensive Cancer Network genetic testing guidelines in identifying African American breast cancer patients with deleterious genetic mutations. | Ademuyiwa FO | Breast cancer research and treatment | 2019 | PMID: 31325073 |
Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. | Weber-Lassalle N | Breast cancer research : BCR | 2018 | PMID: 29368626 |
Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer. | Tedaldi G | Oncotarget | 2017 | PMID: 28423363 |
No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. | Easton DF | Journal of medical genetics | 2016 | PMID: 26921362 |
FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response. | Xie J | PLoS genetics | 2012 | PMID: 22792074 |
Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1. | Cantor SB | Future oncology (London, England) | 2011 | PMID: 21345144 |
Molecular basis of BACH1/FANCJ recognition by TopBP1 in DNA replication checkpoint control. | Leung CC | The Journal of biological chemistry | 2011 | PMID: 21127055 |
Targeting the FANCJ-BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass. | Xie J | Oncogene | 2010 | PMID: 20173781 |
BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. | Gong Z | Molecular cell | 2010 | PMID: 20159562 |
A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function. | De Nicolo A | Clinical cancer research : an official journal of the American Association for Cancer Research | 2008 | PMID: 18628483 |
The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. | Cantor S | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 14983014 |
BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. | Cantor SB | Cell | 2001 | PMID: 11301010 |
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Text-mined citations for rs786203717 ...
HelpRecord last updated Jun 02, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.