ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5467+2T>C
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_007294.4(BRCA1):c.5467+2T>C
Variation ID: 125851 Accession: VCV000125851.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43047641 (GRCh38) [ NCBI UCSC ] 17: 41199658 (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 4, 2014 Feb 14, 2024 Nov 18, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- IVS23+2T>C
- Canonical SPDI
- NC_000017.11:43047640:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- function_uncertain_variant Sequence Ontology [SO:0002220]
- The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5467+2T>C, a CANONICAL SPLICE variant, produced a function score of -0.96, corresponding to a functional classification of INTERMEDIATE. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute, University of Washington]
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
12795 | 14565 |
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 (3) |
criteria provided, single submitter
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Oct 2, 2015 | RCV000112659.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2023 | RCV000162889.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 18, 2023 | RCV000586131.14 |
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
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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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Likely pathogenic
(Mar 24, 2016)
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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: SCV000699241.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.5467+2T>C in a BRCA1 gene is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools via Alamut predict this … (more)
Variant summary: The c.5467+2T>C in a BRCA1 gene is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from ExAC and been reported in affected individual(s) via publications and/or reputable database/clinical laboratory as Likely Pathogenic. Taken together, the variant was classified as Likely Pathogenic until additional information becomes available. (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: SCV000326320.4
First in ClinVar: Apr 04, 2014 Last updated: Dec 11, 2022 |
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Pathogenic
(Aug 31, 2023)
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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: SCV000213376.7
First in ClinVar: Mar 24, 2015 Last updated: Oct 28, 2023 |
Comment:
The c.5467+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 21 in the BRCA1 gene. This alteration occurs … (more)
The c.5467+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 21 in the BRCA1 gene. This alteration occurs at the 3' terminus of the BRCA1 gene and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of this alteration is unknown; however, the impacted BRCT2 domain is critical for protein function (Ambry internal data). This mutation has been reported in several unrelated families suspected of having hereditary breast and ovarian cancer (HBOC) syndrome (Tommasi S et al. Mutat. Res., 2008 Sep;644:64-70; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. One in vitro RNA study demonstrated that this variant resulted in skipping of coding exon 21 (designated as exon 23) (Leman R et al. Nucleic Acids Res, 2018 09;46:7913-7923). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Nov 18, 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: SCV001415044.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 22 of the BRCA1 gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects a donor splice site in intron 22 of the BRCA1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs80358009, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18694767, 29446198). ClinVar contains an entry for this variant (Variation ID: 125851). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 20104584, 21922593, 24504028). 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
(-)
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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: SCV000145522.1
First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014 |
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: in vitro
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Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
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Brotman Baty Institute, University of Washington
Accession: SCV001237491.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
INTERMEDIATE:-0.956031369061015
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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function_uncertain_variant
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Method citation(s):
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Brotman Baty Institute, University of Washington
Accession: SCV001237491.1
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Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5467+2T>C, a CANONICAL SPLICE variant, produced a function score of -0.96, corresponding to a functional classification of … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5467+2T>C, a CANONICAL SPLICE variant, produced a function score of -0.96, corresponding to a functional classification of INTERMEDIATE. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. (less)
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort. | Leman R | Nucleic acids research | 2018 | PMID: 29750258 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic. | Ahlborn LB | Breast cancer research and treatment | 2015 | PMID: 25724305 |
Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. | Cunningham JM | Scientific reports | 2014 | PMID: 24504028 |
Assessment of human Nter and Cter BRCA1 mutations using growth and localization assays in yeast. | Millot GA | Human mutation | 2011 | PMID: 21922593 |
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 |
Molecular and in silico analysis of BRCA1 and BRCA2 variants. | Tommasi S | Mutation research | 2008 | PMID: 18694767 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. | Kawai H | Oncogene | 2002 | PMID: 12400015 |
BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. | Ye Q | The Journal of cell biology | 2001 | PMID: 11739404 |
Functional assay for BRCA1: mutagenesis of the COOH-terminal region reveals critical residues for transcription activation. | Hayes F | Cancer research | 2000 | PMID: 10811118 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. | Friedman LS | Nature genetics | 1994 | PMID: 7894493 |
https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
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Text-mined citations for rs80358009 ...
HelpRecord last updated Apr 20, 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.