ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5333-36_5406+400del
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.5333-36_5406+400del
Variation ID: 267601 Accession: VCV000267601.28
- Type and length
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Deletion, 510 bp
- Location
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Cytogenetic: 17q21.31 17: 43048721-43049230 (GRCh38) [ NCBI UCSC ] 17: 41200738-41201247 (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 1, 2014 Aug 25, 2024 Jun 11, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- IVS21-36del510
- Canonical SPDI
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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
Help
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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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13029 | 14833 |
Conditions - Germline
Condition
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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
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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
Help
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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Pathogenic (3) |
reviewed by expert panel
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Oct 2, 2015 | RCV000258284.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2020 | RCV002347982.2 | |
Pathogenic (1) |
reviewed by expert panel
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Jun 11, 2024 | RCV004567818.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2023 | RCV004696900.1 |
Submissions - Germline
Classification
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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
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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
(Jun 11, 2024)
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reviewed by expert panel
Method: curation
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BRCA1-related cancer predisposition
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004101428.2 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024 |
Comment:
The c.5333-36_5406+400del variant in BRCA1 is a large deletion variant. This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD … (more)
The c.5333-36_5406+400del variant in BRCA1 is a large deletion variant. This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). This variant has been previously reported as deletion exon 22 (legacy exon numbering) in PMIDs: 9354803, 18431737, 22544547, and 24065545. Deletion of exon 21 variant is predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (sequence upstream of BRCA1 p.Leu1854 is disrupted) (PVS1 met). The ENIGMA BRCA1/BRCA2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant within BRCA1 exon 23 (PTC occurs before p.I1855) (PM5_Strong (PTC)). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC)). (less)
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000326279.4
First in ClinVar: Nov 06, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Feb 20, 2020)
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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: SCV002646842.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.5333-36_5406+400del510 pathogenic mutation, results from a deletion of 510 nucleotides at positions 5333-36 to 5406+400, spans coding exon 20 of the BRCA1 gene, and … (more)
The c.5333-36_5406+400del510 pathogenic mutation, results from a deletion of 510 nucleotides at positions 5333-36 to 5406+400, spans coding exon 20 of the BRCA1 gene, and causes a translational frameshift with a predicted alternate stop codon. This specific deletion was first characterized as a recurrent finding in Dutch breast cancer families (Petrij-Bosch A et al. Nat. Genet., 1997 Nov;17:341-5). The deletion co-segregated with disease in all families identified and linkage analysis supported a founder effect in the Dutch population. Additional studies have identified this 510bp deletion in other high risk breast/ovarian cancer families (Engert S et al. Hum. Mutat., 2008 Jul;29:948-58; Rudnicka H et al. Mol. Biol. Rep., 2013 Dec;40:6619-23). Of note, this deletion is also designated as exon 22 del and g.168752_169261del in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function due to a translational frameshift leading to premature truncation, or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Nov 02, 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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196889.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Dec 30, 1999)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145464.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 31
Geographic origin: Netherlands
Observation 3:
Number of individuals with the variant: 11
Ethnicity/Population group: Caucasian
Geographic origin: Netherlands
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Germany
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European, Non Jewish German
Observation 6:
Number of individuals with the variant: 1
Ethnicity/Population group: Dutch
Observation 7:
Number of individuals with the variant: 8
Ethnicity/Population group: Western European
Observation 8:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Ashkenazi
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Pathogenic
(Aug 26, 2022)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV002588835.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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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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Large BRCA1 and BRCA2 genomic rearrangements in Polish high-risk breast and ovarian cancer families. | Rudnicka H | Molecular biology reports | 2013 | PMID: 24065545 |
Clinical significance of large rearrangements in BRCA1 and BRCA2. | Judkins T | Cancer | 2012 | PMID: 22544547 |
MLPA screening in the BRCA1 gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases. | Engert S | Human mutation | 2008 | PMID: 18431737 |
Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH). | Staaf J | Human mutation | 2008 | PMID: 18330910 |
BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. | Petrij-Bosch A | Nature genetics | 1997 | PMID: 9354803 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c5a3fb71-22c6-4f15-bbf5-51f07ad6eff3 | - | - | - | - |
Text-mined citations for rs1555574977 ...
HelpRecord last updated Oct 08, 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.