ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8948_8953+5del
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.8948_8953+5del
Variation ID: 141449 Accession: VCV000141449.16
- Type and length
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Deletion, 11 bp
- Location
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Cytogenetic: 13q13.1 13: 32379507-32379517 (GRCh38) [ NCBI UCSC ] 13: 32953644-32953654 (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 Mar 24, 2015 May 1, 2024 Jun 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8948_8953+5del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000059.3:c.8948_8953+5delATTCAGGTAAG NC_000013.11:g.32379510_32379520del NC_000013.10:g.32953647_32953657del NG_012772.3:g.69031_69041del LRG_293:g.69031_69041del LRG_293t1:c.8948_8953+5del - Protein change
- Other names
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- Canonical SPDI
- NC_000013.11:32379506:AAGATTCAGGTAAG:AAG
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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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18938 | 19097 |
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
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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Pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2020 | RCV000129964.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 17, 2023 | RCV000236901.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 2, 2015 | RCV000238747.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2023 | RCV001849927.12 |
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
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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
(Nov 23, 2015)
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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: SCV000293590.10
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 |
Comment:
This variant is denoted BRCA2 c.8948_8953+5del11 and consists of a deletion of 11 nucleotides at the exon/intron boundary of exon 22. The normal sequence, with … (more)
This variant is denoted BRCA2 c.8948_8953+5del11 and consists of a deletion of 11 nucleotides at the exon/intron boundary of exon 22. The normal sequence, with the bases that are deleted in braces, is AAAG[del11]tatg where the capital letters are exonic and the lower case are intronic. This variant, also known as BRCA2 c.8948_8953+5del using alternate nomenclature, destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Functional studies using a minigene assay have demonstrated that this variant causes aberrant splicing (Acedo 2014). Based on the currently available information, we consider BRCA2 c.8948_8953+5del11 to be a pathogenic variant. (less)
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Pathogenic
(Jul 21, 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: SCV002570879.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: BRCA2 c.8948_8953+5del11 is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: BRCA2 c.8948_8953+5del11 is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5 splicing donor site. Four predict the variant creates a cryptic 5 donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Acedo_2015). The variant was absent in 248098 control chromosomes (gnomAD). c.8948_8953+5del11 has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (LaDuca_2017, Rebbeck_2018). These data indicate that the variant may be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (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, 2
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: SCV000328003.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(May 17, 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: SCV000296606.3
First in ClinVar: Aug 01, 2016 Last updated: Jan 06, 2024 |
Comment:
The BRCA2 c.8948_8953+5del (p.Asp2983_Ser2984del) variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has been reported in the published … (more)
The BRCA2 c.8948_8953+5del (p.Asp2983_Ser2984del) variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has been reported in the published literature in an experimental study that supports this variant impacts BRCA2 mRNA splicing (PMID: 25382762 (2015)). Additionally, the variant has been reported in families with increased risk for breast and/or ovarian cancer (PMIDs: 29446198 (2019), 28150238 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 14, 2023)
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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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Invitae
Accession: SCV002123431.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25382762). ClinVar contains an entry for this variant (Variation ID: 141449). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 22 (c.8948_8953+5del) of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). (less)
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Pathogenic
(Feb 14, 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: SCV000184788.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.8948_8953+5del11 intronic variant (also known as 9176del11), results from a deletion of 11 nucleotides between positions 8948 and 8953+5, which involves the canonical splice … (more)
The c.8948_8953+5del11 intronic variant (also known as 9176del11), results from a deletion of 11 nucleotides between positions 8948 and 8953+5, which involves the canonical splice site after coding exon 21 of the BRCA2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Further, this alteration has been shown to result in aberrant splicing, using a minigene assay (Acedo A et al. Hum. Mutat., 2015 Feb;36:210-21). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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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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Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. | Patel VL | Cancer research | 2020 | PMID: 31723001 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. | Acedo A | Human mutation | 2015 | PMID: 25382762 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs276174915 ...
HelpRecord last updated Sep 17, 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.