ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5194-12G>A
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.5194-12G>A
Variation ID: 55451 Accession: VCV000055451.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43057147 (GRCh38) [ NCBI UCSC ] 17: 41209164 (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 Jun 17, 2024 Jun 11, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- IVS19-12G>A
- Canonical SPDI
- NC_000017.11:43057146: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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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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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
12938 | 14728 |
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
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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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Nov 17, 2023 | RCV000048851.16 | |
Pathogenic (3) |
reviewed by expert panel
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Oct 2, 2015 | RCV000077608.19 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 26, 2021 | RCV000583637.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762996.10 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2019 | RCV001171437.11 | |
Pathogenic (1) |
reviewed by expert panel
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Jun 11, 2024 | RCV004566894.1 |
Submissions - Germline
Classification
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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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Pathogenic
(Jun 11, 2024)
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reviewed by expert panel
Method: curation
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BRCA1-related cancer predisposition
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004101452.3 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024 |
Comment:
The c.5194-12G>A variant is an intronic variant occurring in intron 19 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer … (more)
The c.5194-12G>A variant is an intronic variant occurring in intron 19 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.96, predicting an impact on splicing (score threshold >0.20) (PP3 met). This variant was reported to result in aberrant mRNA splicing by partial retention of intron 19 (PMIDs: 21673748, 21394826). Another study reported the same aberration as well as exon 20 skipping, however it also reported a higher proportion of full length transcript (PMID: 31843900) (PVS1 (RNA) not applied due to conflicting evidence). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1126348153 (based on Cosegregation LR=6.5; Pathology LR=12.7; Co-occurrence LR=1.3; Family History LR=10799731), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PP4_Very strong). (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Breast-ovarian cancer, familial, susceptibility to, 1 Pancreatic cancer, susceptibility to, 4 Fanconi anemia, complementation group S
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893441.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Apr 26, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000688548.4
First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022 |
Comment:
This variant causes a G to A nucleotide substitution at the -12 position of intron 18 of the BRCA1 gene. RNA studies have shown that … (more)
This variant causes a G to A nucleotide substitution at the -12 position of intron 18 of the BRCA1 gene. RNA studies have shown that this variant causes out-of-frame splicing, resulting in expected premature truncation (PMID: 21394826, 21673748, 23278966, 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least 3 individuals affected with breast cancer (PMID: 23278966, 25682074; Color internal data) and also reported to have segregation and family history likelihood ratios for pathogenicity of 532.1 and 363.1, respectively (PMID: 21394826). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Nov 17, 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: SCV000076864.8
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 18 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. … (more)
This sequence change falls in intron 18 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 17924331, 23278966, 25682074). ClinVar contains an entry for this variant (Variation ID: 55451). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21394826, 21673748; Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 21, 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: SCV002643767.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.5194-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 18 in the BRCA1 gene. This alteration has … (more)
The c.5194-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 18 in the BRCA1 gene. This alteration has been classified as as a pathogenic mutation by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton DF et al. Am. J. Hum .Genet. 2007 Nov; 81(5):873-83; Whiley PJ et al. Hum. Mutat. 2011 Jun; 32(6):678-87). Multiple, independent RNA based assays indicate that this variant creates a cryptic splice acceptor site that leads to the insertion of 10 nucleotides and, consequently, a predicted protein frameshift (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun; 32(6):678-87; Théry JC et al. Eur. J. Hum. Genet. 2011 Oct; 19(10):1052-8; Wong-Brown MW et al. Clin. Genet. 2013 Nov; 84(5):505-6). This nucleotide position is highly conserved in available vertebrate species. Of note, this alteration is also designated as IVS19-12G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 07, 2017)
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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: SCV000699219.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
Comment:
Variant summary: The BRCA1 c.5194-12G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. … (more)
Variant summary: The BRCA1 c.5194-12G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 2/5 splice prediction tools predict that this variant creates a novel 3' splicing acceptor site. This prediction was confirmed by two independent studies by sequencing cDNA from the patients carrying the variant of interest (Whiley_2011, Wong-Brown_2013). The studies showed that the altered splicing led to the inclusion of 10bp intronic sequence generating a downstream frameshift mutation (p.His1732Phefs). This variant has been reported in multiple patients with breast cancer and family history of HBOC. This variant is absent in 121410 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including an expert panel. Taken together, this variant is 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, 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: SCV000326205.4
First in ClinVar: Sep 29, 2015 Last updated: Dec 11, 2022 |
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Uncertain significance
(May 29, 2002)
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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: SCV000145385.1
First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 3:
Number of individuals with the variant: 2
Ethnicity/Population group: Western European
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Pathogenic
(Sep 01, 2019)
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no assertion criteria provided
Method: research
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Hereditary breast and ovarian cancer syndrome
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
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King Laboratory, University of Washington
Accession: SCV001251348.1
First in ClinVar: Jun 08, 2020 Last updated: Jun 08, 2020
Comment:
Transcript analysis by cBROCA
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Likely pathogenic
(Feb 11, 2014)
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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
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000109411.5
First in ClinVar: Dec 23, 2013 Last updated: Sep 29, 2015 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228863.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Likely pathogenic and reported on 02-11-2014 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Likely pathogenic and reported on 02-11-2014 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Breast carcinoma (present)
Age: 60-69 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Myriad Genetics, Inc.
Date variant was reported to submitter: 2014-02-11
Testing laboratory interpretation: Likely pathogenic
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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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BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. | Li A | Gynecologic oncology | 2018 | PMID: 30078507 |
DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer. | Flower KJ | Epigenetics | 2015 | PMID: 26727311 |
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. | Wong-Brown MW | Breast cancer research and treatment | 2015 | PMID: 25682074 |
cDNA analysis of the BRCA1 unclassified variant c.5194-12G>A. | Wong-Brown MW | Clinical genetics | 2013 | PMID: 23278966 |
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. | Théry JC | European journal of human genetics : EJHG | 2011 | PMID: 21673748 |
Comprehensive prediction of mRNA splicing effects of BRCA1 and BRCA2 variants. | Mucaki EJ | Human mutation | 2011 | PMID: 21523855 |
Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary. | Whiley PJ | Human mutation | 2011 | PMID: 21394826 |
Risk-reducing surgery for ovarian cancer: outcomes in 300 surgeries suggest a low peritoneal primary risk. | Evans DG | European journal of human genetics : EJHG | 2009 | PMID: 19367322 |
Human Splicing Finder: an online bioinformatics tool to predict splicing signals. | Desmet FO | Nucleic acids research | 2009 | PMID: 19339519 |
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. | Yeo G | Journal of computational biology : a journal of computational molecular cell biology | 2004 | PMID: 15285897 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e65d531b-8a68-477f-8c2e-03dd7faf26c8 | - | - | - | - |
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Text-mined citations for rs80358079 ...
HelpRecord last updated Jun 30, 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.