ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.100G>T (p.Glu34Ter)
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.100G>T (p.Glu34Ter)
Variation ID: 51041 Accession: VCV000051041.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32319109 (GRCh38) [ NCBI UCSC ] 13: 32893246 (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 20, 2024 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.100G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Glu34Ter nonsense NC_000013.11:g.32319109G>T NC_000013.10:g.32893246G>T NG_012772.3:g.8630G>T NG_017006.2:g.1255C>A LRG_293:g.8630G>T LRG_293t1:c.100G>T LRG_293p1:p.Glu34Ter U43746.1:n.328G>T - Protein change
- E34*
- Other names
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- Canonical SPDI
- NC_000013.11:32319108: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
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 (1) |
criteria provided, single submitter
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Jan 1, 2020 | RCV000043711.13 | |
Pathogenic (5) |
reviewed by expert panel
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Sep 8, 2016 | RCV000113128.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2023 | RCV000222288.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 7, 2023 | RCV000496610.16 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 19, 2018 | RCV000657625.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762914.10 |
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
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(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: SCV000300294.2
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
(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: SCV000326482.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Jun 26, 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: SCV001734037.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over twenty individuals with a personal and/or family history of breast or ovarian cancer (PMID: 16683254, 29446198, 29483665) and in an individual affected with breast and prostate cancer (PMID: 29433453). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001301). 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
(Dec 07, 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: SCV001592378.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu34*) 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.Glu34*) 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 and/or ovarian cancer (PMID: 16683254). ClinVar contains an entry for this variant (Variation ID: 51041). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Malignant tumor of prostate Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893326.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Mar 19, 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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GeneDx
Accession: SCV000779368.2
First in ClinVar: Jul 09, 2018 Last updated: Mar 13, 2019 |
Comment:
This variant is denoted BRCA2 c.100G>T at the cDNA level and p.Glu34Ter (E34X) at the protein level. The substitution creates a nonsense variant, which changes … (more)
This variant is denoted BRCA2 c.100G>T at the cDNA level and p.Glu34Ter (E34X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also defined as BRCA2 328G>T using alternate nomenclature, has been reported in association with breast and/or ovarian cancer (van der Hout 2006, Teixeira 2018), as well as in at least one male with prostate and breast cancer (Ibrahim 2018). This variant is considered pathogenic. (less)
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Pathogenic
(Jan 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary Breast Carcinoma
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000296806.3
First in ClinVar: Feb 06, 2014 Last updated: Apr 24, 2020 |
Comment:
This is a single base substitution, replacing the Glutamate at position 34 of the BRCA2 protein by a Termination codon. It results in a truncated … (more)
This is a single base substitution, replacing the Glutamate at position 34 of the BRCA2 protein by a Termination codon. It results in a truncated non-functional protein. Truncating variants in the BRCA2 gene are known to be pathogenic. This mutation has been previously described in mutation databases (https://research.nhgri.nih.gov/projects/bic) as pathogenic. (less)
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Pathogenic
(Dec 15, 2017)
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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: SCV000888969.2
First in ClinVar: Mar 13, 2019 Last updated: Jan 03, 2022 |
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Pathogenic
(Jan 02, 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: SCV000694493.2
First in ClinVar: Aug 07, 2017 Last updated: Feb 13, 2022 |
Comment:
Variant summary: BRCA2 c.100G>T (p.Glu34X) 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.100G>T (p.Glu34X) 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 251030 control chromosomes. c.100G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, van der Hout_2006, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) 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
(May 25, 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: SCV000275329.7
First in ClinVar: May 29, 2016 Last updated: Jul 08, 2023 |
Comment:
The p.E34* pathogenic mutation (also known as c.100G>T), located in coding exon 2 of the BRCA2 gene, results from a G to T substitution at … (more)
The p.E34* pathogenic mutation (also known as c.100G>T), located in coding exon 2 of the BRCA2 gene, results from a G to T substitution at nucleotide position 100. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This mutation has been described in two Dutch families at increased risk for hereditary breast and ovarian cancer (HBOC) syndrome (van der Hout AH et al. Hum. Mutat. 2006 Jul; 27(7):654-66), and in a male breast cancer patient (Ibrahim M et al. BMC Cancer 2018 02;18(1):179). 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(5):593-620). RNA studies have demonstrated that this substitution results in abnormal splicing that includes two in-frame transcripts that splice out this alteration and the premature stop codon from final transcript: one transcript that removes the first 15 amino acids from coding exon 2 and one that results in the complete loss of coding exon 2 that is known to be deleterious (Ambry internal data; Caputo SM et al. Oncotarget 2018 Apr;9(25):17334-17348). Current data suggests that the presence of these transcripts is not expected to rescue function. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 23, 2003)
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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: SCV000146161.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Near Eastern
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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: SCV000587539.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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Pathogenic
(-)
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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: SCV000733206.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906285.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955684.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV004243615.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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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 |
Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer. | Caputo SM | Oncotarget | 2018 | PMID: 29707112 |
The association between cancer family history and ovarian cancer risk in BRCA1/2 mutation carriers: can it be explained by the mutation position? | Teixeira N | European journal of human genetics : EJHG | 2018 | PMID: 29483665 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Male BRCA mutation carriers: clinical characteristics and cancer spectrum. | Ibrahim M | BMC cancer | 2018 | PMID: 29433453 |
Comprehensive prediction of mRNA splicing effects of BRCA1 and BRCA2 variants. | Mucaki EJ | Human mutation | 2011 | PMID: 21523855 |
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 |
A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. | van der Hout AH | Human mutation | 2006 | PMID: 16683254 |
Text-mined citations for rs80358391 ...
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.