ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter)
Variation ID: 52919 Accession: VCV000052919.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32398438 (GRCh38) [ NCBI UCSC ] 13: 32972575 (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 Feb 14, 2024 Oct 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.9925G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Glu3309Ter nonsense NC_000013.11:g.32398438G>T NC_000013.10:g.32972575G>T NG_012772.3:g.87959G>T LRG_293:g.87959G>T LRG_293t1:c.9925G>T LRG_293p1:p.Glu3309Ter U43746.1:n.10153G>T - Protein change
- E3309*
- Other names
- NM_000059.4(BRCA2):c.9925G>T
- p.Glu3309Ter
- Canonical SPDI
- NC_000013.11:32398437:G: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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18542 | 18699 |
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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Uncertain significance (4) |
reviewed by expert panel
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Oct 12, 2023 | RCV000112825.17 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 13, 2023 | RCV000496671.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 7, 2023 | RCV000657637.11 | |
Likely pathogenic (1) |
no assertion criteria provided
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Oct 3, 2003 | RCV000735634.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2023 | RCV001184568.15 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Uncertain significance
(Oct 12, 2023)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
Accession: SCV004101448.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The c.9925G>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon … (more)
The c.9925G>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic acid at amino acid 3309 (p.Glu3309Ter). 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). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting). (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: SCV000328177.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Likely pathogenic
(Nov 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766459.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: BRCA2 c.9925G>T (p.Glu3309X) 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.9925G>T (p.Glu3309X) 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. This variant is creates a stop codon one amino acid downstream of the common pathogenic variant p.Tyr3308X. The variant was absent in 251252 control chromosomes. c.9925G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Kuznetsov_2008, Smith_2019). These data indicate that the variant may be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function (Kuznetsov_2008, Biswas_2012, Mesman_2018). The most pronounced variant effect results in a 25% reduction in HDR activity as well as increased sensitivity to DNA-damaging agents (Mesman_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, citing the variant with conflicting assessments as pathogenic (n = 2), likely pathogenic (n = 2), and unknown significance (n = 2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jun 05, 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: SCV000677709.2
First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022 |
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Uncertain significance
(Jul 06, 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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Ambry Genetics
Accession: SCV002691029.2
First in ClinVar: Nov 29, 2022 Last updated: Oct 28, 2023 |
Comment:
The p.E3309* variant (also known as c.9925G>T), located in coding exon 26 of the BRCA2 gene, results from a G to T substitution at nucleotide … (more)
The p.E3309* variant (also known as c.9925G>T), located in coding exon 26 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9925. This changes the amino acid from a glutamic acid to a stop codon within coding exon 26. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRCA2 and is not expected to trigger nonsense-mediated mRNA decay. Functional studies have found conflicting evidence for this variant, with this variant being shown to cause hypersensitivity to DNA damaging agents (Kuznetsov SG et al. Nat. Med., 2008 Aug;14:875-81), but also demonstrated to maintain a high rate of homology directed repair efficiency (Mesman RLS et al. Genet. Med., 2019 02;21:293-302). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Nov 13, 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: SCV001511659.4
First in ClinVar: Mar 14, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu3309*) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Glu3309*) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 110 amino acid(s) of the BRCA2 protein. 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 and/or endometrial cancer (PMID: 29446198, 32914019). ClinVar contains an entry for this variant (Variation ID: 52919). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 06, 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: SCV001350586.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 27 of the BRCA2 gene, creating a premature translation stop signal in the last coding exon. Functional studies … (more)
This variant changes 1 nucleotide in exon 27 of the BRCA2 gene, creating a premature translation stop signal in the last coding exon. Functional studies in mouse embryonic stem cells have provided conflicting conclusions on variant impact on the protein function (PMID 18607349, 29988080). Although both studies indicated increased sensitivity to DNA damaging agents, the mutant protein was able to complement BRCA2-deficiency and showed only partially reduced homology-directed recombination activity. This variant has been reported in an individual affected with ovarian cancer (PMID: 18607349) and has been identified in 1 family among the CIMBA participants (PMID: 29446198).. 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). 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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Uncertain significance
(Nov 07, 2023)
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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: SCV000779381.3
First in ClinVar: Jul 09, 2018 Last updated: Nov 25, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation as the last 110 amino acids are lost, although loss-of-function variants have not been reported downstream of … (more)
Nonsense variant predicted to result in protein truncation as the last 110 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 10153G>T; This variant is associated with the following publications: (PMID: 22678057, 26332594, 29988080, 29446198, 18607349, 32914019, 10733923) (less)
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Pathogenic
(Apr 12, 1999)
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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: SCV000145733.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
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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: SCV000588017.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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Likely pathogenic
(Oct 03, 2003)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000863772.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 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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Endometrial Cancers in BRCA1 or BRCA2 Germline Mutation Carriers: Assessment of Homologous Recombination DNA Repair Defects. | Smith ES | JCO precision oncology | 2019 | PMID: 32914019 |
The functional impact of variants of uncertain significance in BRCA2. | Mesman RLS | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29988080 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
Genome annotation by shotgun inactivation of a native gene in hemizygous cells: application to BRCA2 with implication of hypomorphic variants. | Ghosh S | Human mutation | 2015 | PMID: 25451944 |
Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. | Biswas K | Human molecular genetics | 2012 | PMID: 22678057 |
Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. | Kuznetsov SG | Nature medicine | 2008 | PMID: 18607349 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c0020d30-3b67-46e8-8a83-90ddcfd98a45 | - | - | - | - |
Text-mined citations for rs80359251 ...
HelpRecord last updated Apr 20, 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.