ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.9246dup (p.Lys3083fs)
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.9246dup (p.Lys3083fs)
Variation ID: 254630 Accession: VCV000254630.19
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32380134-32380135 (GRCh38) [ NCBI UCSC ] 13: 32954271-32954272 (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 Sep 25, 2016 May 1, 2024 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.9246dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Lys3083fs frameshift NM_000059.3:c.9246dupG NC_000013.11:g.32380135dup NC_000013.10:g.32954272dup NG_012772.3:g.69656dup LRG_293:g.69656dup LRG_293t1:c.9246dup LRG_293p1:p.Lys3083fs - Protein change
- K3083fs
- Other names
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- Canonical SPDI
- NC_000013.11:32380134:G:GG
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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 |
18726 | 18884 |
Conditions - Germline
Condition
Help
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 (1) |
reviewed by expert panel
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Sep 8, 2016 | RCV000241025.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 24, 2023 | RCV000460386.17 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 20, 2015 | RCV000483716.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2022 | RCV000569477.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2023 | RCV003387517.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 30, 2023 | RCV003463713.1 |
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
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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
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: SCV000301364.2
First in ClinVar: Sep 25, 2016 Last updated: Sep 25, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Aug 20, 2015)
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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: SCV000567698.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This duplication of one nucleotide in BRCA2 is denoted c.9246dupG at the cDNA level and p.Lys3083GlufsX28 (K3083EfsX28) at the protein level. The normal sequence, with … (more)
This duplication of one nucleotide in BRCA2 is denoted c.9246dupG at the cDNA level and p.Lys3083GlufsX28 (K3083EfsX28) at the protein level. The normal sequence, with the base that is duplicated in braces, is TTGT[G]AAAA. The duplication causes a frameshift, which changes a Lysine to a Glutamic Acid at codon 3083, and creates a premature stop codon at position 28 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic. (less)
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Pathogenic
(Apr 16, 2019)
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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: SCV001361749.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: BRCA2 c.9246dupG (p.Lys3083GlufsX28) 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.9246dupG (p.Lys3083GlufsX28) 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. The variant was absent in 248582 control chromosomes (gnomAD). c.9246dupG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Cock-Rada 2018). 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 ClinVar submissions from clinical diagnostic laboratories and one expert panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 24, 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: SCV000549713.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys3083Glufs*28) 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.Lys3083Glufs*28) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 254630). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 20, 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: SCV000668737.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.9246dupG pathogenic mutation, located in coding exon 23 of the BRCA2 gene, results from a duplication of G at nucleotide position 9246, causing a … (more)
The c.9246dupG pathogenic mutation, located in coding exon 23 of the BRCA2 gene, results from a duplication of G at nucleotide position 9246, causing a translational frameshift with a predicted alternate stop codon (p.K3083Efs*28). One study detected this mutation in 5/85 Colombian breast cancer patients who were tested with a multi-gene panel (Cock-Rada AM et al. Fam. Cancer, 2018 Jan;17:23-30). 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
(Jul 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group D1
Affected status: unknown
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004099249.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
PVS1, PS4, PM2
Secondary finding: yes
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Pathogenic
(May 30, 2023)
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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: SCV004216102.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 05, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004362801.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant inserts 1 nucleotide in exon 24 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 five individuals affected with breast cancer (PMID: 28528518). 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
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
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: SCV000592264.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA2 p.Lys3083GlufsX28 variant was not identified in the literature nor was it identified in dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant … (more)
The BRCA2 p.Lys3083GlufsX28 variant was not identified in the literature nor was it identified in dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, LOVD, ARUP Laboratories BRCA Mutations Database, COSMIC, the ClinVar database, GeneInsight COGR database, the BIC database, and BRCA Share. The p.Lys3083GlufsX28 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3083 and leads to a premature stop codon 28 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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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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A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
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 |
Text-mined citations for rs886038189 ...
HelpRecord last updated May 27, 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.