ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.51_52del (p.Arg18fs)
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.51_52del (p.Arg18fs)
Variation ID: 51814 Accession: VCV000051814.22
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 13q13.1 13: 32316509-32316510 (GRCh38) [ NCBI UCSC ] 13: 32890646-32890647 (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 Feb 6, 2014 Apr 20, 2024 Apr 22, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.51_52del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg18fs frameshift NM_000059.3:c.49_50delAC frameshift NC_000013.11:g.32316509AC[1] NC_000013.10:g.32890646AC[1] NG_012772.3:g.6030AC[1] NG_017006.2:g.3852GT[1] LRG_293:g.6030AC[1] LRG_293t1:c.51_52del U43746.1:n.279_280delAC - Protein change
- R18fs
- Other names
- 279delAC
- Canonical SPDI
- NC_000013.11:32316508:ACAC:AC
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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
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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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Jul 1, 2016 | RCV000044604.10 | |
Pathogenic (3) |
reviewed by expert panel
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Apr 22, 2016 | RCV000113063.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 8, 2021 | RCV000131871.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2016 | RCV000219019.9 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2024 | RCV000496563.17 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353628.9 |
Submissions - Germline
Classification
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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
(Apr 22, 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: SCV000282398.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Jan 21, 2016)
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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: SCV000279262.9
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
This deletion of 2 nucleotides in BRCA2 is denoted c.51_52delAC at the cDNA level and p.Arg18LeufsX12 (R18LfsX12) at the protein level. The normal sequence, with … (more)
This deletion of 2 nucleotides in BRCA2 is denoted c.51_52delAC at the cDNA level and p.Arg18LeufsX12 (R18LfsX12) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAC[AC]GCTG. The deletion causes a frameshift, which changes an Arginine to a Leucine at codon 18, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.51_52delAC, previously reported as 277delAC and 279delAC, did not rescue the embryonic stem cell lethality in an in vitro functional assay, and was also observed to segregate with disease in at least one large hereditary breast/ovarian cancer family, consistent with its role as a pathogenic variant (Kuznetsov 2008, Tavtigian 1996). we consider this variant to be 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: SCV000327129.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Jul 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000296839.1
First in ClinVar: Feb 06, 2014 Last updated: Feb 06, 2014 |
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Pathogenic
(Apr 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: SCV000694829.2
First in ClinVar: Aug 07, 2017 Last updated: May 21, 2021 |
Comment:
Variant summary: BRCA2 c.51_52delAC (p.Arg18LeufsX12) 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.51_52delAC (p.Arg18LeufsX12) 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 251254 control chromosomes. c.51_52delAC 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, 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
(Jun 08, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683670.4
First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 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. A functional study has reported that this variant impacts BRCA2 function in complementing Brca2-deficient mouse embryonic stem cells (PMID: 18607349). This variant has been reported in at least five individuals affected with breast cancer and ovarian cancer (PMID: 8589730, 10070953, 20104584, 34072659) and in suspected hereditary breast and ovarian cancer families (PMID: 22430266, 26534844, 28324225). This variant has been reported to segregate with male and female breast cancer and ovarian cancer in a large pedigree with a LOD score of 5.06 (PMID: 8589730, 9245992). 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
(Mar 28, 2019)
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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: SCV000186926.7
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The c.51_52delAC pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 51 and … (more)
The c.51_52delAC pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 51 and 52, causing a translational frameshift with a predicted alternate stop codon (p.R18Lfs*12). This pathogenic mutation has been observed in multiple individuals with breast, ovarian, and male breast cancer (Tavtigian SV et al. Nat. Genet.1996 Mar;12(3):333-7; Csokay B et al. Cancer Res.1999 Mar; 59(5):995-8; Borg A et al. Hum. Mutat. 2010 Mar;31(3):E1200-40; Ding YC et al. Breast Cancer Res. Treat. 2011 Apr; 126(3):771-8; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as 277delAC and 279delAC in published literature. 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
(May 19, 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: SCV001223158.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51814). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51814). This variant is also known as 277delAC and 279delAC. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 8589730, 20104584, 26534844, 28324225). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg18Leufs*12) 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). (less)
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Pathogenic
(Apr 01, 2024)
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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: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848613.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg18LeufsX12 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 2 males with breast cancer. This variant segregated with disease … (more)
The p.Arg18LeufsX12 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 2 males with breast cancer. This variant segregated with disease in one large family (exact numbers not disclosed; Tavtigian 1996 PMID: 8589730, Easton 1997 PMID: 9245992, Csokay 1999 PMID: 10070953, Seymour 2008 PMID: 18092194, Borg 2010 PMID: 20104584, Ding 2011 PMID: 20927582, Finkelman 2012 PMID: 22430266, Li 2016 PMID: 26534844, Meisel 2017 PMID: 28324225, Toss 2019 PMID: 30736435, Shao 2020 PMID: 31742824, Solano 2021 PMID: 34072659). This variant has also been identified in 0.0005% (2/418050) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org, v4.0.0). In vitro functional studies support an impact on protein function as this variant did not rescue embryonic stem cell lethality in an in vitro functional assay (Kuznetsov 2008 PMID: 18607349). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 18 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51814). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PS3_Supporting. (less)
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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,
unknown
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146071.2
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 3
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
Observation 3:
Number of individuals with the variant: 1
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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: SCV000587530.1 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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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: SCV000591655.2 First in ClinVar: Aug 07, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Arg18LeufsX12 variant was identified in 2 of 1974 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Finkelman 2012, Tavtigian 1996). The … (more)
The p.Arg18LeufsX12 variant was identified in 2 of 1974 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Finkelman 2012, Tavtigian 1996). The variant was also identified in dbSNP (ID: rs80359483) “With pathogenic allele”, HGMD, LOVD, the ClinVar database (classified as a pathogenic variant by BIC and Ambry Genetics), and the BIC database (5X with clinical importance). A functional assay by Kuznetsov (2008) found that this mutation could not rescue mouse embryonic stem cell lethality, supporting its deleterious phenotype. The p.Arg18LeufsX12 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 18 and leads to a premature stop codon 12 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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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 |
Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals. | Shao D | Cancer science | 2020 | PMID: 31742824 |
Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies. | Toss A | Cancers | 2019 | PMID: 30736435 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. | Meisel C | Archives of gynecology and obstetrics | 2017 | PMID: 28324225 |
Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families. | Li J | Journal of medical genetics | 2016 | PMID: 26534844 |
Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. | Finkelman BS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22430266 |
Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. | Ding YC | Breast cancer research and treatment | 2011 | PMID: 20927582 |
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 |
Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. | Kuznetsov SG | Nature medicine | 2008 | PMID: 18607349 |
Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations. | Seymour IJ | Breast cancer research and treatment | 2008 | PMID: 18092194 |
High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history. | Csokay B | Cancer research | 1999 | PMID: 10070953 |
Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. | Easton DF | American journal of human genetics | 1997 | PMID: 9245992 |
The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. | Tavtigian SV | Nature genetics | 1996 | PMID: 8589730 |
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Text-mined citations for rs80359483 ...
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.