ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.5217_5220del (p.Thr1738_Tyr1739insTer)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.5217_5220del (p.Thr1738_Tyr1739insTer)
Variation ID: 51820 Accession: VCV000051820.28
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 13q13.1 13: 32339569-32339572 (GRCh38) [ NCBI UCSC ] 13: 32913706-32913709 (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 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.5217_5220del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Thr1738_Tyr1739insTer nonsense NM_000059.3:c.5217_5220delTTTA NC_000013.11:g.32339572_32339575del NC_000013.10:g.32913709_32913712del NG_012772.3:g.29093_29096del LRG_293:g.29093_29096del U43746.1:n.5445_5448delTTTA - Protein change
- Other names
- 5445del4
- Canonical SPDI
- NC_000013.11:32339568:TTATTTA:TTA
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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 |
18955 | 19114 |
Conditions - Germline
Condition
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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
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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) |
reviewed by expert panel
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Sep 8, 2016 | RCV000113400.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2023 | RCV000219606.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 23, 2024 | RCV000497280.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 14, 2023 | RCV000507175.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2024 | RCV004566824.1 |
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
(Sep 08, 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: SCV000300847.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Jul 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000605820.2
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Comment:
The p.Tyr1739X variant in BRCA2 has been reported 5 individuals with BRCA2-assoc iated cancers (Stuppia 2003, Susswein 2015, Breast Cancer Information Core (BIC) ). It … (more)
The p.Tyr1739X variant in BRCA2 has been reported 5 individuals with BRCA2-assoc iated cancers (Stuppia 2003, Susswein 2015, Breast Cancer Information Core (BIC) ). It was also absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This nonsense variant is a result of a deletion of 4 bases, which creates a premature termination codon at position 1739. This alteration is then predicted to lead to a truncated or absen t protein. Heterozygous loss of function of the BRCA2 gene is an established dis ease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as pathogenic on September 8, 2016 by the ClinGen-approv ed ENIGMA expert panel (ClinVar SCV000300847.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on predicted impact to the protein and absence from controls. (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 23, 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: SCV000210761.6
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Nonsense 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 … (more)
Nonsense 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 (PMID: 30322717, 12872265, 32341426); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5445_5448delTTTA and 5445del4; This variant is associated with the following publications: (PMID: 12872265, 26681312, 30322717, 31447099, 11802209, 32073954, 33047316, 29446198, 10717622, 9150154, 32341426) (less)
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Pathogenic
(Jan 19, 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: SCV000694843.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Comment:
Variant summary: The BRCA2 c.5217_5220delTTTA (p.Tyr1739fs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense … (more)
Variant summary: The BRCA2 c.5217_5220delTTTA (p.Tyr1739fs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, it seems to be in a mutation hot spot, where other pathogenic variants have been reported such as c.5218_5223del7, c.5213_5216del4, and c.5217_5221del5. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Apr 14, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591507.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51820). This variant is also known as 5445del4. This premature translational stop signal has been observed in individual(s) with prostate cancer, ovarian cancer, or breast cancer (PMID: 9150154, 10717622, 11802209, 12872265, 26681312). This sequence change creates a premature translational stop signal (p.Tyr1739*) 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). (less)
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Pathogenic
(Dec 28, 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: SCV000274521.5
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.5217_5220delTTTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5217 to … (more)
The c.5217_5220delTTTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5217 to 5220, causing a translational frameshift with a predicted alternate stop codon (p.Y1739*). This alteration has identified in individuals diagnosed with prostate cancer, ovarian cancer and breast cancer (Stuppia L et al. Hum Mutat. 2003 Aug;22(2):178-9; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; De Talhouet S et al. Sci Rep, 2020 04;10:7073). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this mutation is also designated as 5445del4 in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Mar 22, 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: SCV005058352.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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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: SCV000327175.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Apr 04, 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: SCV000688921.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (Color data), ovarian cancer (PMID: 26681312) and prostate cancer (PMID: 12872265). 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 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: SCV000146569.1
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
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Central/Eastern European
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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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Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. | De Talhouet S | Scientific reports | 2020 | PMID: 32341426 |
Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
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 |
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 |
BRCA1 and BRCA2 mutations in breast/ovarian cancer patients from central Italy. | Stuppia L | Human mutation | 2003 | PMID: 12872265 |
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. | Meindl A | International journal of cancer | 2002 | PMID: 11802209 |
Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. | Malone KE | Cancer | 2000 | PMID: 10717622 |
Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. | Håkansson S | American journal of human genetics | 1997 | PMID: 9150154 |
Text-mined citations for rs80359494 ...
HelpRecord last updated Oct 13, 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.