This variant causes an A>T nucleotide substitution at the -2 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional study reported this variant as defective in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in at least one individual with triple-negative breast cancer (PMID: 30350268) and additional individuals considered at-risk for breast and/or ovarian cancer (PMID: 22798144, 29673794). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5333-2A>T
Germline
Classification
Help
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.
(5)
Help
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/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.5333-2A>T
Variation ID: 55536 Accession: VCV000055536.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43049196 (GRCh38) [ NCBI UCSC ] 17: 41201213 (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 Sep 27, 2014 May 1, 2024 Jan 17, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- -
- Other names
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IVS21-2A>T
- Canonical SPDI
- NC_000017.11:43049195:T:A
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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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functionally_abnormal; Sequence Ontology [ SO:0002218]The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5333-2A>T, a CANONICAL SPLICE variant, produced a function score of -1.75, corresponding to a functional classification of LOSS_OF_FUNCTION. 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
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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 |
13044 | 14850 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Dec 22, 2021 | RCV000077616.14 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2023 | RCV000580882.15 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Dec 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683294.4
First in ClinVar: Feb 19, 2018 Last updated: Jan 15, 2022 |
Comment:
This variant causes an A>T nucleotide substitution at the -2 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this … (more)
This variant causes an A>T nucleotide substitution at the -2 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional study reported this variant as defective in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in at least one individual with triple-negative breast cancer (PMID: 30350268) and additional individuals considered at-risk for breast and/or ovarian cancer (PMID: 22798144, 29673794). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
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Pathogenic
(Dec 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004217011.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003911973.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The c.5333-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 20 in the BRCA1 gene. This alteration … (more)
The c.5333-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 20 in the BRCA1 gene. This alteration has been reported in several Korean breast cancer cohorts (Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Kim DH et al. BMC Med Genet, 2017 Mar;18:38) and in 1 of 999 Korean triple negative breast cancer patients undergoing BRCA1/2 genetic testing (Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395). This variant was also reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the 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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Likely pathogenic
(Nov 30, 2010)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000109419.2
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
|
|
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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: SCV001243129.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-1.74958397786638
|
Comment:
Comment:
The c.5333-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 20 in the BRCA1 gene. This alteration has been reported in several Korean breast cancer cohorts (Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Kim DH et al. BMC Med Genet, 2017 Mar;18:38) and in 1 of 999 Korean triple negative breast cancer patients undergoing BRCA1/2 genetic testing (Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395). This variant was also reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the 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.
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. |
|---|---|---|---|---|
|
functionally_abnormal
|
Method citation(s):
|
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Brotman Baty Institute, University of Washington
Accession: SCV001243129.1
|
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5333-2A>T, a CANONICAL SPLICE variant, produced a function score of -1.75, corresponding to a functional classification of … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5333-2A>T, a CANONICAL SPLICE variant, produced a function score of -1.75, corresponding to a functional classification of LOSS_OF_FUNCTION. 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)
|
Comment:
This variant causes an A>T nucleotide substitution at the -2 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional study reported this variant as defective in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in at least one individual with triple-negative breast cancer (PMID: 30350268) and additional individuals considered at-risk for breast and/or ovarian cancer (PMID: 22798144, 29673794). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The c.5333-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 20 in the BRCA1 gene. This alteration has been reported in several Korean breast cancer cohorts (Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Kim DH et al. BMC Med Genet, 2017 Mar;18:38) and in 1 of 999 Korean triple negative breast cancer patients undergoing BRCA1/2 genetic testing (Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395). This variant was also reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea. | Ryu JM | Breast cancer research and treatment | 2019 | PMID: 30350268 |
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Identification of large genomic rearrangement of BRCA1/2 in high risk patients in Korea. | Kim DH | BMC medical genetics | 2017 | PMID: 28351343 |
| Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. | Kim H | Breast cancer research and treatment | 2012 | PMID: 22798144 |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
Text-mined citations for rs397509264 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.