The c.5333-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 20 of the BRCA1 gene. This alteration has been shown to result in a transcript lacking coding exon 20 (total exon 21) in RNA studies (Ambry internal data; Aspessos A. et al. Cancer Genet 2018 01;220:1-12). This transcript is not expected to trigger nonsense-mediated mRNA decay, however, the impacted region is critical for protein function (Ambry internal data). In addition, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5333-1G>A
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.
(6)
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
6
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.5333-1G>A
Variation ID: 55533 Accession: VCV000055533.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43049195 (GRCh38) [ NCBI UCSC ] 17: 41201212 (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 29, 2015 May 1, 2024 Nov 17, 2020 - HGVS
- ... more HGVS ... less HGVS
- Protein change
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- Other names
- -
- Canonical SPDI
- NC_000017.11:43049194:C: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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functionally_abnormal; Sequence Ontology [ SO:0002218]The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5333-1G>A, a CANONICAL SPLICE variant, produced a function score of -2.27, 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.
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- 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. |
|---|---|---|---|---|
| Likely pathogenic (3) |
criteria provided, single submitter
|
Aug 12, 2014 | RCV000169281.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 8, 2017 | RCV000758843.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 9, 2020 | RCV001384038.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 17, 2020 | RCV002345349.9 |
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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Pathogenic
(Sep 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000887722.2
First in ClinVar: Mar 14, 2019 Last updated: Jan 03, 2022 |
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Likely pathogenic
(Aug 12, 2014)
|
criteria provided, single submitter
Method: literature only
|
Breast-ovarian cancer, familial 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220588.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Nov 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002640809.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.5333-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 20 of the BRCA1 gene. This alteration … (more)
The c.5333-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 20 of the BRCA1 gene. This alteration has been shown to result in a transcript lacking coding exon 20 (total exon 21) in RNA studies (Ambry internal data; Aspessos A. et al. Cancer Genet 2018 01;220:1-12). This transcript is not expected to trigger nonsense-mediated mRNA decay, however, the impacted region is critical for protein function (Ambry internal data). In addition, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Nov 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001583404.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (30209399, 29310832). This variant has been observed in individuals affected with breast cancer (PMID: 19941162, 29310832, 28294317). This variant is also known as IVS21-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55533). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 20 of the BRCA1 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Medical Genetics, Medical University Pleven
Accession: SCV004100894.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
|
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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: SCV001243130.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-2.2703966552698
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (30209399, 29310832). This variant has been observed in individuals affected with breast cancer (PMID: 19941162, 29310832, 28294317). This variant is also known as IVS21-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55533). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 20 of the BRCA1 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
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
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Method citation(s):
|
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Brotman Baty Institute, University of Washington
Accession: SCV001243130.1
|
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5333-1G>A, a CANONICAL SPLICE variant, produced a function score of -2.27, corresponding to a functional classification of … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5333-1G>A, a CANONICAL SPLICE variant, produced a function score of -2.27, 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:
The c.5333-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 20 of the BRCA1 gene. This alteration has been shown to result in a transcript lacking coding exon 20 (total exon 21) in RNA studies (Ambry internal data; Aspessos A. et al. Cancer Genet 2018 01;220:1-12). This transcript is not expected to trigger nonsense-mediated mRNA decay, however, the impacted region is critical for protein function (Ambry internal data). In addition, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (30209399, 29310832). This variant has been observed in individuals affected with breast cancer (PMID: 19941162, 29310832, 28294317). This variant is also known as IVS21-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55533). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 20 of the BRCA1 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Comprehensive BRCA mutation analysis in the Greek population. Experience from a single clinical diagnostic center. | Apessos A | Cancer genetics | 2018 | PMID: 29310832 |
| The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next-generation sequencing. | Lang GT | International journal of cancer | 2017 | PMID: 28294317 |
| High-throughput resequencing in the diagnosis of BRCA1/2 mutations using oligonucleotide resequencing microarrays. | Schroeder C | Breast cancer research and treatment | 2010 | PMID: 19941162 |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
Text-mined citations for rs80358126 ...
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.