ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.426-12_426-8del
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.
Uncertain significance(8); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.426-12_426-8del
Variation ID: 51619 Accession: VCV000051619.48
- Type and length
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Deletion, 5 bp
- Location
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Cytogenetic: 13q13.1 13: 32326086-32326090 (GRCh38) [ NCBI UCSC ] 13: 32900223-32900227 (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 Sep 16, 2024 Apr 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.426-12_426-8del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_000059.3:c.426-12_426-8del5 intron variant NM_000059.3:c.426-12_426-8delGTTTT NC_000013.11:g.32326089_32326093del NC_000013.10:g.32900226_32900230del NG_012772.3:g.15610_15614del LRG_293:g.15610_15614del LRG_293t1:c.426-12_426-8del - Protein change
- Other names
- IVS4-12del5
- Canonical SPDI
- NC_000013.11:32326085:TTTGTTTT:TTT
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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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18938 | 19097 |
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 15, 2024 | RCV000044380.36 | |
Uncertain significance (3) |
criteria provided, single submitter
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Sep 21, 2015 | RCV000113566.10 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Apr 9, 2024 | RCV000203666.18 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jun 29, 2023 | RCV000496561.12 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 7, 2021 | RCV001022168.16 |
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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Uncertain significance
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744382.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Uncertain significance
(May 27, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001339313.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This variant causes a deletion of 5 nucleotides in intron 4 of the BRCA2 gene. The variant is also known as IVS4-12del5, c.654-12_654-8delGTTTT, and c.426-12_8del5 … (more)
This variant causes a deletion of 5 nucleotides in intron 4 of the BRCA2 gene. The variant is also known as IVS4-12del5, c.654-12_654-8delGTTTT, and c.426-12_8del5 in the literature. Experimental RNA studies of this variant have demonstrated a partial impact on splicing, increasing the skipping of exon 5 and producing a truncated protein in mutant cells (PMID: 19070627, 20215541, 21394826, 24212087, 30883759, 32133419). However, significant baseline expression of the exon 5 skipped transcript in normal cells may limit the variant's causal impact on disease (PMID: 27060066, 29774201, 32133419). This variant has been reported in individuals affected with breast cancer in the literature, but also in unaffected individuals (PMID: 10923033, 18446624, 19070627, 30675319, 16162645). This variant has also been observed to co-occur with pathogenic variants in BRCA1 (PMID: 18446624, Color Internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jan 15, 2024)
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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: SCV000072393.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
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Likely benign
(Apr 09, 2024)
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criteria provided, single submitter
Method: curation
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Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV005184338.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): absent from controls (gnomAD v2/3), PP3 (supporting pathogenic): SpliceAI ≥ … (more)
According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): absent from controls (gnomAD v2/3), PP3 (supporting pathogenic): SpliceAI ≥ 0.2, BP5 (medium benign): Combined LR (Parsons 2019): 0.1359 (cutoff 0.23:1<LR<0.05:1), BS2 (medium benign): Nix 2020 (PMID: 35050751): in 2 individuals with no known features of Fanconi anemia confirmed in trans with BRCA2 c.7719dupA or c.9257-1G>C (less)
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Uncertain significance
(Feb 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000210806.16
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate aberrant splicing leading to skipping of exon 5 resulting in a truncated BRCA2 protein, but also show the presence of wild-type … (more)
Published functional studies demonstrate aberrant splicing leading to skipping of exon 5 resulting in a truncated BRCA2 protein, but also show the presence of wild-type transcript indicating an incomplete splice defect (PMID: 19070627, 20215541, 21394826, 30883759); Observed in individuals with a personal and/or family history of BRCA2-related cancers, some of whom also carried a pathogenic variant in BRCA1 or BRCA2, and reported to occur in trans with a pathogenic BRCA2 variant in individuals without known features of Fanconi anemia (PMID: 18446624, 19070627, 26681312, 30675319, 35050751); Not observed at significant frequency in large population cohorts (gnomAD); Also known as BRCA2 654-12_654-8delGTTTT and IVS4-12del5; This variant is associated with the following publications: (PMID: 27060066, 30675319, 31642931, 23893897, 16162645, 20215541, 21394826, 19070627, 32133419, 31131967, 18446624, 24212087, 31980526, 30883759, 10923033, 26681312, 21520333, 35050751) (less)
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Uncertain significance
(Jan 18, 2019)
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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: SCV001133786.3
First in ClinVar: Jan 04, 2020 Last updated: Jan 01, 2022 |
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Uncertain significance
(Dec 07, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002533861.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.426-15_426-11delTTTGT variant has been reported in heterozygosity in at least 5 individuals with breast and ovarian cancer (PMID: 16162645, 19070627, 31980526, 30675319, 18446624). … (more)
The BRCA2 c.426-15_426-11delTTTGT variant has been reported in heterozygosity in at least 5 individuals with breast and ovarian cancer (PMID: 16162645, 19070627, 31980526, 30675319, 18446624). It is also known as IVS4-12del5 in the literature. This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 51619). Mini-gene assays and mRNA studies have shown that the variant increases the rate of exon 5 skipping (PMID: 30883759, 31642931, 19070627). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jun 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919003.4
First in ClinVar: Jun 02, 2019 Last updated: Jul 29, 2023 |
Comment:
Variant summary: BRCA2 c.426-12_426-8delGTTTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: BRCA2 c.426-12_426-8delGTTTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict the variant weakens a 3' acceptor site. In addition, a recent computational study predicted a high probability of splicing impact (Leman_2018). Several publications reported experimental evidence that this variant affects mRNA splicing, by increasing exon 5 skipping (predicted to result in a frameshift), and consequently decreasing the expression of the full-length transcript (e.g., Zhang_2009, Sanz_2010, Whiley_2011, Whiley_2014, Lattimore_2018, Fraile-Bethencourt_2019). However, a more recent study found that this aberrant splicing is inefficient and the percent splicing index (PSI) was determined to be ~20% in positive controls (vs. ~10% in healthy controls) (Landrith_2020); the amount of normal transcript needed for normal BRCA2 function is unknown (Nix_2020). The variant was absent in 249586 control chromosomes (gnomAD). c.426-12_426-8delGTTTT has been reported in the literature in individuals affected with breast cancer, as well as unaffected individuals (e.g., Zhang_2009, Whiley_2011, Susswein_2015). These reports do not allow any conclusion about variant significance. Multiple co-occurrences with other pathogenic variants have been reported (BRCA2 c.9257-1G>C [NHGRI BIC database, Nix_2020]; BRCA2 c.7248del, p.H2417TfsX50 [LOVD database]; BRCA1 c.5152+1G>T [Loughrey_2008]; BRCA2 c.7719dupA, p.W2574MfsX10 [Nix_2020]), providing supporting evidence for a benign role. Particularly, Nix et al (2020) report carriers of the variant did not have a personal or family history consistent with pathogenicity and they specify that the variant was found to co-occur in trans with two different pathogenic variants in BRCA2 in individuals with no known features of Fanconi anemia. The following publications have been ascertained in the context of this evaluation (PMID: 26992833, 27060066, 30675319, 30883759, 21702907, 31642931, 29774201, 29750258, 18446624, 20215541, 26681312, 24212087, 21394826, 19070627, 32133419, 35050751). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; 7 submitters classified the variant as VUS, and 1 submitter classified it as likely benign. Based on the evidence outlined above, the variant was re-classified as VUS-possibly benign. (less)
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Uncertain significance
(Aug 20, 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: SCV001183869.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.426-12_426-8delGTTTT intronic variant, results from a deletion of 5 intronic nucleotides upstream of coding exon 4 in the BRCA2 gene. This alteration, designated as … (more)
The c.426-12_426-8delGTTTT intronic variant, results from a deletion of 5 intronic nucleotides upstream of coding exon 4 in the BRCA2 gene. This alteration, designated as IVS4-12del5, was identified in a family with melanoma, breast and pancreatic cancer and segregated with disease in this family. Furthermore, a breast tumor from this family showed loss of heterozygosity for BRCA2 (Zhang L et al. Mutat. Res. 2009 Apr;663:84-9). This variant has been shown to cause incomplete exon skipping, leading to a frameshift and creation of a premature alternative stop codon (Zhang L et al. Mutat. Res. 2009 Apr;663:84-9; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Whiley PJ et al. Clin. Chem. 2014 Feb;60:341-52). In addition, internal, quantitative RNA studies have demonstrated this alteration results in a substantial amount of abnormal splicing. However, this alteration has also been reported in trans with other pathogenic BRCA2 variants in patients of unknown age and phenotype who do not have overt symptoms of Fanconi Anemia (Ambry internal data; Nix, P et al. JCO Prec. Onc. 2020 June;4:790-35). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Aug 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747693.18
First in ClinVar: Jul 10, 2021 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 2
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Uncertain significance
(Feb 20, 2004)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146817.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Uncertain significance
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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not specified
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587547.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
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: SCV000733210.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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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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Functional RNA Studies Are a Useful Tool in Variant Classification but Must Be Used With Caution: A Case Study of One BRCA2 Variant. | Nix P | JCO precision oncology | 2020 | PMID: 35050751 |
Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes. | Landrith T | NPJ precision oncology | 2020 | PMID: 32133419 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer. | Karam R | JAMA network open | 2019 | PMID: 31642931 |
Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays. | Fraile-Bethencourt E | The Journal of pathology | 2019 | PMID: 30883759 |
BRCA mutation screening and patterns among high-risk Lebanese subjects. | Farra C | Hereditary cancer in clinical practice | 2019 | PMID: 30675319 |
Investigation of Experimental Factors That Underlie BRCA1/2 mRNA Isoform Expression Variation: Recommendations for Utilizing Targeted RNA Sequencing to Evaluate Potential Spliceogenic Variants. | Lattimore VL | Frontiers in oncology | 2018 | PMID: 29774201 |
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 |
Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples. | Fackenthal JD | Journal of medical genetics | 2016 | PMID: 27060066 |
The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations. | Diederichs S | EMBO molecular medicine | 2016 | PMID: 26992833 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Comparison of mRNA splicing assay protocols across multiple laboratories: recommendations for best practice in standardized clinical testing. | Whiley PJ | Clinical chemistry | 2014 | PMID: 24212087 |
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
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 |
A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. | Sanz DJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2010 | PMID: 20215541 |
cDNA analysis demonstrates that the BRCA2 intronic variant IVS4-12del5 is a deleterious mutation. | Zhang L | Mutation research | 2009 | PMID: 19070627 |
Histopathological features of 'BRCAX' familial breast cancers in the kConFab resource. | Loughrey M | Pathology | 2008 | PMID: 18446624 |
Lymphocytes of BRCA1 and BRCA2 germ-line mutation carriers, with or without breast cancer, are not abnormally sensitive to the chromosome damaging effect of moderate folate deficiency. | Beetstra S | Carcinogenesis | 2006 | PMID: 16162645 |
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Text-mined citations for rs276174844 ...
HelpRecord last updated Sep 17, 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.