ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5332+1G>A
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.5332+1G>A
Variation ID: 55527 Accession: VCV000055527.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43051062 (GRCh38) [ NCBI UCSC ] 17: 41203079 (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 May 1, 2024 Apr 3, 2016 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- IVS21+1G>A
- Canonical SPDI
- NC_000017.11:43051061:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on RNA splicing Variation Ontology [VariO:0362]
- functionally_abnormal Sequence Ontology [SO:0002218]
- The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5332+1G>A, a CANONICAL SPLICE variant, produced a function score of -2.61, 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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 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 |
12876 | 14661 |
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, multiple submitters, no conflicts
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Jul 26, 2022 | RCV000048933.19 | |
Pathogenic (6) |
reviewed by expert panel
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Apr 3, 2016 | RCV000112615.17 | |
Pathogenic (3) |
criteria provided, single submitter
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Oct 3, 2016 | RCV000508361.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2022 | RCV000565923.14 |
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
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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Pathogenic
(Apr 03, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000282245.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.5278_5332del transcript (encoding predicted non-functional protein).
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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: SCV000326268.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Jun 26, 2023)
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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:
unknown
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Baylor Genetics
Accession: SCV004215078.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 27, 2022)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000904691.2
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the +1 position of intron 20 of the BRCA1 gene. RNA studies have reported that … (more)
This variant causes a G to A nucleotide substitution at the +1 position of intron 20 of the BRCA1 gene. RNA studies have reported that this variant causes the out-of-frame skipping of exon 20 resulting in premature termination (PMID: 19629752, 24667779) and a functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least five individuals affected with breast or ovarian cancer (PMID: 19629752, 26541979, 26997744, 27083178, 28993434, 30715675, 33471991, 35464868; Leiden Open Variation Database DB-ID BRCA1_000567). This variant has been identified in 1/251352 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Nov 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002025902.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
Testing laboratory: National Health Laboratory Service (NHLS)
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Pathogenic
(Oct 03, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600415.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 03, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)
Accession: SCV002104296.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Observation 1:
Age: 40-49 years
Sex: female
Geographic origin: Algeria
Observation 2:
Age: 50-59 years
Sex: female
Geographic origin: Algeria
Observation 3:
Age: 30-39 years
Sex: female
Geographic origin: Algeria
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Pathogenic
(Jul 26, 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: SCV002570847.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: BRCA1 c.5332+1G>A 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: BRCA1 c.5332+1G>A 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 5 splicing donor site. Experimental evidence supports these predictions demonstrating that this variant affects mRNA splicing, leading to skipping of exon 20 (Colombo_2013). The variant allele was found at a frequency of 4e-06 in 251352 control chromosomes (gnomAD). c.5332+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function through employment of a cell-survival assay in a population of edited haploid HAP1 cells as a measure of functional HDR pathway, determined the variant to be non-functional (Findlay_2018). Seven ClinVar submitters including an expert panel (ENIGMA) (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
(Jun 26, 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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Invitae
Accession: SCV000076946.10
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 55527). This variant is also known as c.5451+1G>A. Disruption of this splice site has been observed … (more)
ClinVar contains an entry for this variant (Variation ID: 55527). This variant is also known as c.5451+1G>A. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11084537, 16324400, 19629752, 27083178). This variant is present in population databases (rs80358041, gnomAD 0.006%). This sequence change affects a donor splice site in intron 20 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in skipping of exon 20 (also known as exon 21) and introduces a premature termination codon (PMID: 23451180, 24667779; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 29, 2021)
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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: SCV000668384.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.5332+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 19 of the BRCA1 gene. This mutation was … (more)
The c.5332+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 19 of the BRCA1 gene. This mutation was found to be de novo in a female diagnosed with bilateral breast cancers at ages 38 and 43 (Edwards E et al. Fam. Cancer. 2009; 8(4):479-82) and has also been reported in a Chinese female with ovarian cancer (Hasmad HN et al. Gynecol. Oncol. 2015 Nov) and in an Algerian female diagnosed with triple negative breast cancer at age 34 (Henouda S et al. Dis. Markers 2016; Epub 2016 Feb 22). RNA splicing assays have shown this alteration to cause coding exon 19 (exon 21 in literature) skipping (Ambry internal data; Colombo M et al. PLoS ONE. 2013; 8(2): e57173; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8). 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(7726):217-222). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954966.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jun 21, 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: SCV000145457.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744053.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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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: SCV001243075.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-2.61004528526674
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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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effect on RNA splicing
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University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)
Accession: SCV002104296.1
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functionally_abnormal
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Method citation(s):
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Brotman Baty Institute, University of Washington
Accession: SCV001243075.1
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Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5332+1G>A, a CANONICAL SPLICE variant, produced a function score of -2.61, corresponding to a functional classification of … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5332+1G>A, a CANONICAL SPLICE variant, produced a function score of -2.61, 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)
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.834265 |
Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | PMID: 35464868 |
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 |
BRCA1 and BRCA2 Germline Mutation Analysis in Hereditary Breast/Ovarian Cancer Families from the Aures Region (Eastern Algeria): First Report. | Mehemmai C | Pathology oncology research : POR | 2020 | PMID: 30715675 |
Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. | Wen WX | Journal of medical genetics | 2018 | PMID: 28993434 |
Frequency of germline DNA genetic findings in an unselected prospective cohort of triple-negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial. | González-Rivera M | Breast cancer research and treatment | 2016 | PMID: 27083178 |
Contribution of BRCA1 and BRCA2 Germline Mutations to Early Algerian Breast Cancer. | Henouda S | Disease markers | 2016 | PMID: 26997744 |
Evaluation of germline BRCA1 and BRCA2 mutations in a multi-ethnic Asian cohort of ovarian cancer patients. | Hasmad HN | Gynecologic oncology | 2016 | PMID: 26541979 |
Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations. | Golmard L | Oncogene | 2016 | PMID: 26028024 |
Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic. | Ahlborn LB | Breast cancer research and treatment | 2015 | PMID: 25724305 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Functional characterization of BRCA1 gene variants by mini-gene splicing assay. | Steffensen AY | European journal of human genetics : EJHG | 2014 | PMID: 24667779 |
Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. | Colombo M | PloS one | 2013 | PMID: 23451180 |
A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer. | Garcia-Casado Z | BMC medical genetics | 2011 | PMID: 21989022 |
Identification of a de novo BRCA1 mutation in a woman with early onset bilateral breast cancer. | Edwards E | Familial cancer | 2009 | PMID: 19629752 |
BRCA1 germline mutations and tumor characteristics in Chinese women with familial or early-onset breast cancer. | Chen W | Breast cancer research and treatment | 2009 | PMID: 18512148 |
[Mutational analysis of BRCA1 and BRCA2 genes in early-onset breast cancer patients in Shanghai]. | Song CG | Zhonghua yi xue za zhi | 2005 | PMID: 16324400 |
BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect. | Muller D | Familial cancer | 2004 | PMID: 15131401 |
[Germ-line mutations of the BRCA1 gene in northeastern France]. | Fricker JP | Bulletin du cancer | 2000 | PMID: 11084537 |
https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
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Text-mined citations for rs80358041 ...
HelpRecord last updated May 01, 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.