ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7857G>A (p.Trp2619Ter)
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.7857G>A (p.Trp2619Ter)
Variation ID: 38122 Accession: VCV000038122.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32362574 (GRCh38) [ NCBI UCSC ] 13: 32936711 (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 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7857G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Trp2619Ter nonsense NC_000013.11:g.32362574G>A NC_000013.10:g.32936711G>A NG_012772.3:g.52095G>A LRG_293:g.52095G>A LRG_293t1:c.7857G>A LRG_293p1:p.Trp2619Ter U43746.1:n.8085G>A - Protein change
- W2619*
- Other names
- 8085G>A
- Canonical SPDI
- NC_000013.11:32362573: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
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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 (6) |
reviewed by expert panel
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Sep 8, 2016 | RCV000031704.17 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 28, 2023 | RCV000162936.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 12, 2020 | RCV000521372.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 10, 2023 | RCV000496960.16 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2020 | RCV001257551.9 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353730.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2022 | RCV003473212.1 |
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
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: SCV000301211.2
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
(Sep 25, 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: SCV000785585.2
First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016 |
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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: SCV000327746.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Mar 31, 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: SCV004212821.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Feb 28, 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: SCV004362722.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 17 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 17 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 at least five individuals affected with breast and/or ovarian cancer (PMID: 21318380, 26306726, 32438681, 34072659, 35205366) and in a suspected hereditary breast and ovarian cancer family (PMID: 16234499). 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
(Jan 30, 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: SCV001478826.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
Comment:
Variant summary: BRCA2 c.7857G>A (p.Trp2619X) 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.7857G>A (p.Trp2619X) 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 251256 control chromosomes. c.7857G>A has been 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple 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
(Feb 12, 2020)
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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: SCV000618238.3
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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; Truncating … (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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 8085G>A; This variant is associated with the following publications: (PMID: 26681678, 16234499, 26306726, 24670361, 28152038, 27463008, 29446198, 31446535) (less)
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Pathogenic
(May 11, 2022)
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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: SCV000213423.5
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.W2619* pathogenic mutation (also known as c.7857G>A), located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at … (more)
The p.W2619* pathogenic mutation (also known as c.7857G>A), located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7857. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This mutation has previously been reported in multiple individuals with clinical histories suggestive of hereditary breast and/or ovarian cancer (Nanda R et al. JAMA. 2005 Oct;294:1925-33; Hansen TV et al. Fam. Cancer. 2011 Jun;10:207-12). 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)
Number of individuals with the variant: 1
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Pathogenic
(Oct 10, 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: SCV001588437.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp2619*) 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.Trp2619*) 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 a personal or family history of breast and/or ovarian cancer (PMID: 16234499, 21318380, 26306726). ClinVar contains an entry for this variant (Variation ID: 38122). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 20, 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: SCV000147203.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Italian
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Pathogenic
(May 15, 2009)
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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: SCV000054311.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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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: SCV000587915.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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Pathogenic
(Sep 01, 2020)
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no assertion criteria provided
Method: provider interpretation
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Rhabdomyosarcoma
Affected status: yes
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434377.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
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: SCV000592152.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Trp2619X variant has been reported in the literature in 1/310 proband chromosomes from an individual in a family with hereditary breast and ovariant cancer. … (more)
The p.Trp2619X variant has been reported in the literature in 1/310 proband chromosomes from an individual in a family with hereditary breast and ovariant cancer. However, no control chromosomes were tested to establish its frequency in the general population (Nanda 2005). It was also reported in the BIC (x1) database. The variant leads to a premature stop codon at position 2619 which is predicted to cause premature truncation or absent protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism for hereditary breast and ovariant cancer. In summary, based on the above information, this variant is classified as pathogenic. (less)
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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: SCV004243784.1
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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Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation. | Vietri MT | Genes | 2022 | PMID: 35205366 |
Study of the Genetic Variants in BRCA1/2 and Non-BRCA Genes in a Population-Based Cohort of 2155 Breast/Ovary Cancer Patients, Including 443 Triple-Negative Breast Cancer Patients, in Argentina. | Solano AR | Cancers | 2021 | PMID: 34072659 |
Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. | Li H | Journal of the National Cancer Institute | 2021 | PMID: 33372952 |
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. | Azzollini J | European journal of internal medicine | 2016 | PMID: 27062684 |
Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. | Minucci A | Expert review of molecular diagnostics | 2015 | PMID: 26306726 |
Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations. | Hansen TV | Familial cancer | 2011 | PMID: 21318380 |
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 |
Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. | Nanda R | JAMA | 2005 | PMID: 16234499 |
Text-mined citations for rs80359011 ...
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.