ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.1773_1776del (p.Ile591fs)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.1773_1776del (p.Ile591fs)
Variation ID: 51190 Accession: VCV000051190.31
- Type and length
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Microsatellite, 4 bp
- Location
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Cytogenetic: 13q13.1 13: 32333246-32333249 (GRCh38) [ NCBI UCSC ] 13: 32907383-32907386 (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 Aug 11, 2024 Apr 22, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.1773_1776del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Ile591fs frameshift NM_000059.3:c.1773_1776delTTAT NC_000013.11:g.32333247TTAT[1] NC_000013.10:g.32907384TTAT[1] NG_012772.3:g.22768TTAT[1] LRG_293:g.22768TTAT[1] U43746.1:n.2001_2004delTTAT - Protein change
- I591fs
- Other names
- 2001del4
- 2000del4
- 2000_2003delTTTA
- Canonical SPDI
- NC_000013.11:32333245:TTTATTTAT:TTTAT
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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
Help
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
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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18935 | 19094 |
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
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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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Jan 28, 2024 | RCV000043880.22 | |
Pathogenic (7) |
reviewed by expert panel
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Apr 22, 2016 | RCV000112966.18 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000160268.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 7, 2024 | RCV000213388.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2020 | RCV001310171.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2024 | RCV003460563.2 |
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 22, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000282360.1
First in ClinVar: Jan 02, 2016 Last updated: Jan 02, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Oct 22, 2018)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450407.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Feb 25, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296721.2
First in ClinVar: Jan 02, 2016 Last updated: Jan 03, 2022 |
Indication for testing: Hereditary breast and ovarian cancer syndrome (HBOC)
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Pathogenic
(Feb 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000677670.2
First in ClinVar: Mar 27, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Sep 15, 2022)
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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: SCV000210715.6
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Kanaan et al., 2003; Thirthagiri et al., 2008; Novakovic et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2001_2004del; This variant is associated with the following publications: (PMID: 18393245, 28993434, 32846166, 30787465, 31825140, 32719484, 26295337, 20104584, 12942367, 28439188, 28888541, 29446198, Bahsi2020[case report], 30702160, 24123850, 30875412, 18627636, 22923021) (less)
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Pathogenic
(Jan 28, 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: SCV000071893.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile591Metfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ile591Metfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12942367, 18393245, 22923021). This variant is also known as 2001delTTAT. ClinVar contains an entry for this variant (Variation ID: 51190). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004216170.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499766.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Apr 18, 2021)
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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: SCV001623181.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: BRCA2 c.1773_1776delTTAT (p.Ile591MetfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA2 c.1773_1776delTTAT (p.Ile591MetfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248932 control chromosomes. c.1773_1776delTTAT has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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, 2
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: SCV000326608.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Feb 06, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242827.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(Jun 13, 2023)
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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: SCV002052184.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 4 nucleotides in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more)
This variant deletes 4 nucleotides in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2001del4 and 2000del4 in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least four individuals affected with breast cancer (PMID: 12942367, 18393245, 18627636, 20174566, 33471991) and in suspected hereditary breast and ovarian cancer families (PMID: 19949876, 21120943, 22923021). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 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
(May 07, 2024)
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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: SCV000274783.8
First in ClinVar: May 29, 2016 Last updated: Aug 11, 2024 |
Comment:
The c.1773_1776delTTAT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1773 to … (more)
The c.1773_1776delTTAT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1773 to 1776, causing a translational frameshift with a predicted alternate stop codon (p.I591Mfs*22). This mutation has been detected in multiple individuals from hereditary breast and/or ovarian cancer cohorts also unselected breast cancer cohorts (Kanaan Y et al. Hum. Genet. 2003 Oct;113:452-60; Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Yildiz T et al. Life Sci 2020 Nov;261:118334; Demir S et al. J BUON;25(3):1337-1347). Of note, this mutation is also designated as 2001del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 18, 2010)
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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: SCV000145930.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Chinese
Geographic origin: Malaysia
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Pathogenic
(May 29, 2002)
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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: SCV000145931.1
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
(Mar 02, 2020)
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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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BRCAlab, Lund University
Accession: SCV004244227.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
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: SCV000587609.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550959.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Number of individuals with the variant: 1
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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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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 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Next Generation Sequencing Reveals High Prevalence of BRCA1 and BRCA2 Variants of Unknown Significance in Early-Onset Breast Cancer in African American Women. | Ricks-Santi L | Ethnicity & disease | 2017 | PMID: 28439188 |
Capillary electrophoresis analysis of conventional splicing assays: IARC analytical and clinical classification of 31 BRCA2 genetic variants. | de Garibay GR | Human mutation | 2014 | PMID: 24123850 |
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families. | Novaković S | International journal of oncology | 2012 | PMID: 22923021 |
EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. | Caux-Moncoutier V | Human mutation | 2011 | PMID: 21120943 |
Use of DNA-damaging agents and RNA pooling to assess expression profiles associated with BRCA1 and BRCA2 mutation status in familial breast cancer patients. | Walker LC | PLoS genetics | 2010 | PMID: 20174566 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
Efficiency of BRCAPRO and Myriad II mutation probability thresholds versus cancer history criteria alone for BRCA1/2 mutation detection. | van Harssel JJ | Familial cancer | 2010 | PMID: 19949876 |
Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer. | Thirthagiri E | Breast cancer research : BCR | 2008 | PMID: 18627636 |
[Analysis of BRCA2 gene mutations among familial and/or early-onset breast cancer patients in eastern Shandong of China]. | Ma ZL | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2008 | PMID: 18393245 |
Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases. | Kanaan Y | Human genetics | 2003 | PMID: 12942367 |
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Text-mined citations for rs80359304 ...
HelpRecord last updated Aug 25, 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.