ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.22_23del (p.Arg8fs)
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.22_23del (p.Arg8fs)
Variation ID: 51267 Accession: VCV000051267.20
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 13q13.1 13: 32316478-32316479 (GRCh38) [ NCBI UCSC ] 13: 32890615-32890616 (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 27, 2014 Feb 28, 2024 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.22_23del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg8fs frameshift NM_000059.3:c.22_23delAG NC_000013.11:g.32316478AG[2] NC_000013.10:g.32890615AG[2] NG_012772.3:g.5999AG[2] NG_017006.2:g.3881CT[2] LRG_293:g.5999AG[2] - Protein change
- R8fs
- Other names
- 250delAG
- Canonical SPDI
- NC_000013.11:32316477:AGAGAG:AGAG
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2023 | RCV000043971.19 | |
Pathogenic (4) |
reviewed by expert panel
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Sep 8, 2016 | RCV000083090.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2021 | RCV001186007.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2021 | RCV001770067.10 |
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
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: SCV000300284.2
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
(Aug 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000605788.2
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
Comment:
The p.Arg8fs variant in BRCA2 has been reported in 1 individual with a BRCA2-ass ociated cancer (Lubinski 2004) and was absent from large population studies, … (more)
The p.Arg8fs variant in BRCA2 has been reported in 1 individual with a BRCA2-ass ociated cancer (Lubinski 2004) and was absent from large population studies, tho ugh the ability of these studies to accurately detect indels may be limited. Thi s variant is predicted to cause a frameshift, which alters the protein?s amino a cid sequence beginning at position 8 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Heterozygous loss of function of the BRCA2 gene is an esta blished disease mechanism in individuals with hereditary breast and ovarian canc er (HBOC). Furthermore, the p.Arg8fs variant was classified as Pathogenic on Sep tember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300284 .2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on predicted impact to the protei n and absence from controls. (less)
Number of individuals with the variant: 2
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Pathogenic
(Apr 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296541.2
First in ClinVar: Sep 27, 2014 Last updated: Jan 03, 2022 |
Indication for testing: Hereditary breast and ovarian cancer syndrome (HBOC)
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Pathogenic
(Jan 15, 2020)
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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: SCV001352334.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 15, 2022 |
Comment:
This variant deletes 2 nucleotides in exon 2 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 2 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 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
(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: SCV000326667.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Jun 23, 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: SCV002727485.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.22_23delAG pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 22 to … (more)
The c.22_23delAG pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 22 to 23, causing a translational frameshift with a predicted alternate stop codon (p.R8Afs*5). This mutation (also designated as 250delAG and c.18_19delAG) has been identified in multiple high-risk breast/ovarian cancer cohorts (Lubinski J et al. Fam Cancer, 2004;3:1-10; Cybulski C et al. Clin Genet, 2015 Oct;88:366-70; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368). In addition, 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
(Jan 21, 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: SCV002004220.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Frameshift 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; Variant … (more)
Frameshift 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; Variant was observed in individuals with Hereditary Breast and Ovarian Cancer (Lubinski 2004, Cybulski 2014, Song 2014, Manchana 2019); 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 18_19delAG and 250delAG; This variant is associated with the following publications: (PMID: 26295337, 25330149, 15131399, 31815095, 31447099, 22762150, 24728189, 26843898) (less)
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Pathogenic
(Dec 22, 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: SCV000071984.9
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg8Alafs*5) 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.Arg8Alafs*5) 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 personal or family history of breast and/or ovarian cancer (PMID: 15131399, 22762150, 25330149, 25556971). This variant is also known as c.18_19delAG and 250delAG. ClinVar contains an entry for this variant (Variation ID: 51267). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 15, 2011)
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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: SCV000115164.3
First in ClinVar: Feb 06, 2014 Last updated: Sep 27, 2014 |
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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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Germline mutations in Thai patients with nonmucinous epithelial ovarian cancer. | Manchana T | World journal of clinical oncology | 2019 | PMID: 31815095 |
Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland. | Wojcik P | Hereditary cancer in clinical practice | 2016 | PMID: 26843898 |
Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer. | Trujillano D | The Journal of molecular diagnostics : JMD | 2015 | PMID: 25556971 |
Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. | Cybulski C | Clinical genetics | 2015 | PMID: 25330149 |
The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. | Song H | Human molecular genetics | 2014 | PMID: 24728189 |
Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO). | Lecarpentier J | Breast cancer research : BCR | 2012 | PMID: 22762150 |
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 |
Cancer variation associated with the position of the mutation in the BRCA2 gene. | Lubinski J | Familial cancer | 2004 | PMID: 15131399 |
Text-mined citations for rs397507623 ...
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.