ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8969G>A (p.Trp2990Ter)
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.8969G>A (p.Trp2990Ter)
Variation ID: 126195 Accession: VCV000126195.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32379765 (GRCh38) [ NCBI UCSC ] 13: 32953902 (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 4, 2014 Feb 14, 2024 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8969G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Trp2990Ter nonsense NC_000013.11:g.32379765G>A NC_000013.10:g.32953902G>A NG_012772.3:g.69286G>A LRG_293:g.69286G>A LRG_293t1:c.8969G>A LRG_293p1:p.Trp2990Ter U43746.1:n.9197G>A - Protein change
- W2990X
- Other names
- 9197G>A
- Canonical SPDI
- NC_000013.11:32379764:G:A
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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
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 | RCV000114025.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2021 | RCV000131050.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 26, 2021 | RCV000425086.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000637796.15 | |
Pathogenic (1) |
criteria provided, single submitter
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May 13, 2022 | RCV003474704.1 |
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
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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: SCV000301326.2
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
(May 12, 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: SCV000600835.2
First in ClinVar: Mar 08, 2017 Last updated: Jan 03, 2022 |
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Pathogenic
(Apr 26, 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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GeneDx
Accession: SCV000516129.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a … (more)
Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Acedo 2012); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with BRCA2-related cancers (Borg 2010, Ellingson 2015, Pal 2015, Dong 2018, Ryu 2019); This variant is associated with the following publications: (PMID: 20104584, 30350268, 32623769, 22632462, 17899372, 26296701, 26287763, 23893897, 30039884, 29202330, 32926152) (less)
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Pathogenic
(May 13, 2022)
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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: SCV004212800.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001426960.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
Comment:
Variant summary: BRCA2 c.8969G>A (p.Trp2990X) 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.8969G>A (p.Trp2990X) 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 250750 control chromosomes. c.8969G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and as a somatic occurrence in at-least one patient with triple negative breast cancer (TNBC) (example, Borg_2010, Ellingson_2015, Pal_2015, Pop_2018, Ryu_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and one 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 14, 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: SCV000185980.7
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The p.W2990* pathogenic mutation (also known as c.8969G>A), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at … (more)
The p.W2990* pathogenic mutation (also known as c.8969G>A), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8969. This changes the amino acid from a tryptophan to a stop codon within coding exon 22. This pathogenic mutation has been reported in multiple women with early-onset and/or familial breast cancer (Borg A et al. Hum. Mutat. 2010 Mar; 31(3):E1200-40; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153(2):435-43; Pal T et al. Cancer 2015 Dec;121(23):4173-80; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Dong L et al. Hum Mutat, 2018 10;39:1442-1455). In addition, studies have shown that c.8969G>A is located in a conserved exonic splice enhancing region and is predicted to enhance cryptic splicing (Pettigrew CA et al. Breast Cancer Res. Treat. 2008 Jul; 110(2):227-34; Acedo A et al. Breast Cancer Res. 2012; 14(3):R87). 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)
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 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: SCV000759275.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp2990*) 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.Trp2990*) 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: 20104584, 26287763, 26296701). This variant is also known as 9197G>A. ClinVar contains an entry for this variant (Variation ID: 126195). 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
(Jan 21, 2010)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000189320.2
First in ClinVar: Sep 30, 2014 Last updated: Sep 30, 2014 |
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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: SCV000147503.1
First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014 |
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: African
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Asian
Geographic origin: Korean
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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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Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer. | Yadav S | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2020 | PMID: 32125938 |
Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea. | Ryu JM | Breast cancer research and treatment | 2019 | PMID: 30350268 |
Detection of novel germline mutations in six breast cancer predisposition genes by targeted next-generation sequencing. | Dong L | Human mutation | 2018 | PMID: 30039884 |
Genetic alterations in sporadic triple negative breast cancer. | Pop LA | Breast (Edinburgh, Scotland) | 2018 | PMID: 29202330 |
Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. | Ellingson MS | Breast cancer research and treatment | 2015 | PMID: 26296701 |
A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. | Pal T | Cancer | 2015 | PMID: 26287763 |
Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. | Acedo A | Human mutation | 2015 | PMID: 25382762 |
Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes. | Acedo A | Breast cancer research : BCR | 2012 | PMID: 22632462 |
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 |
Colocalisation of predicted exonic splicing enhancers in BRCA2 with reported sequence variants. | Pettigrew CA | Breast cancer research and treatment | 2008 | PMID: 17899372 |
Text-mined citations for rs80359148 ...
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.