ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.26del (p.Pro9fs)
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.26del (p.Pro9fs)
Variation ID: 51330 Accession: VCV000051330.29
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32316485 (GRCh38) [ NCBI UCSC ] 13: 32890623 (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 14, 2024 Apr 22, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.26del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Pro9fs frameshift NM_000059.3:c.26delC NC_000013.11:g.32316486del NC_000013.10:g.32890623del NG_012772.3:g.6007del NG_017006.2:g.3879del LRG_293:g.6007del U43746.1:n.254delC - Protein change
- P9fs
- Other names
- 254delC
- Canonical SPDI
- NC_000013.11:32316484:CC:C
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000044041.26 | |
Pathogenic (7) |
reviewed by expert panel
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Apr 22, 2016 | RCV000077284.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2022 | RCV000132408.17 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV000215325.16 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353718.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2019 | RCV001798229.10 |
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
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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: SCV000282371.1
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
(Dec 30, 2015)
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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: SCV000296580.2
First in ClinVar: Jun 24, 2016 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: SCV001350920.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 15, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 2 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide 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: SCV000326745.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Aug 31, 2016)
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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: SCV000489184.2
First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Jun 01, 2023)
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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: SCV000278834.10
First in ClinVar: May 29, 2016 Last updated: Jun 10, 2023 |
Comment:
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gayther et al., 1997; Basham et al., 2002; Evans … (more)
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gayther et al., 1997; Basham et al., 2002; Evans et al., 2008; Tutt et al., 2010; Alsop et al., 2012; Thompson et al., 2012; Frugtniet et al., 2022); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 252delC, 253delC, and 254delC; This variant is associated with the following publications: (PMID: 22711857, 21702907, 14662532, 15131399, 31263054, 8988179, 12036913, 27376475, 23028338, 11879560, 20609467, 17636422, 11044354, 18158280, 27433846, 30787465, 28888541, 32778766, 29922827, 33758026, 34657373) (less)
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Pathogenic
(Jun 12, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002020244.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Apr 23, 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: SCV000694620.2
First in ClinVar: Dec 26, 2017 Last updated: May 23, 2021 |
Comment:
Variant summary: BRCA2 c.26delC (p.Pro9GlnfsX16) 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.26delC (p.Pro9GlnfsX16) 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 251392 control chromosomes. c.26delC has been widely 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. 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
(Aug 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042536.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(Sep 02, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535517.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Pathogenic
(Sep 06, 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: SCV000187500.7
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The c.26delC pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of one nucleotide at position 26, causing a … (more)
The c.26delC pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of one nucleotide at position 26, causing a translational frameshift with a predicted alternate stop codon (p.P9Qfs*16). This mutation has been identified in multiple individuals with breast, ovarian, prostate, and/or pancreatic cancers (Gayther SA et al. Nat. Genet. 1997 Jan;15(1):103-5; Evans DG et al. Fam. Cancer 2008 Jul;7(2):113-7; Alsop K et al. J. Clin. Oncol. 2012 Jul;30(21):2654-63; Thompson ER et al. PLoS Genet. 2012 Sep;8(9):e1002894; Pritchard CC et al. N. Engl. J. Med. 2016 Aug 4;375(5):443-53; Schenkel LC et al. J. Mol. Diagn. 2016 09;18(5):657-667; Hu C et al. JAMA 2018 06;319(23):2401-2409). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as 254delC and 253delC 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
(Dec 15, 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: SCV000072054.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro9Glnfs*16) 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.Pro9Glnfs*16) 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 hereditary breast and ovarian cancer (PMID: 8988179, 11044354, 17636422, 22711857, 23028338). It has also been observed to segregate with disease in related individuals. This variant is also known as 253delC. ClinVar contains an entry for this variant (Variation ID: 51330). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 15, 2007)
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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: SCV000109081.3
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
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Pathogenic
(Feb 20, 2004)
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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: SCV000146029.2
First in ClinVar: Apr 01, 2014 Last updated: Mar 29, 2015 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European
Observation 3:
Number of individuals with the variant: 3
Ethnicity/Population group: Western European
Observation 4:
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: SCV000587527.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 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: SCV000591654.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Pro9GlnfsX16 deletion variant was identified in 4 of 3028 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alsop 2012, … (more)
The p.Pro9GlnfsX16 deletion variant was identified in 4 of 3028 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alsop 2012, Gayther 1997, Weitzel 2003).The variant was also identified in dbSNP (ID: rs80359343) “With pathogenic allele”, HGMD, LOVD, UMD (1X as a causal variant), and the BIC database (7X as clinically important). The p.Pro9GlnfsX16 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 9 and leads to a premature stop codon 16 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)
Number of individuals with the variant: 1
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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: SCV004244036.1
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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Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. | Hu C | JAMA | 2018 | PMID: 29922827 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. | Schenkel LC | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27376475 |
Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. | Thompson ER | PLoS genetics | 2012 | PMID: 23028338 |
BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. | Alsop K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22711857 |
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
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 |
BRCA1/2 mutation analysis in male breast cancer families from North West England. | Evans DG | Familial cancer | 2008 | PMID: 17636422 |
Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. | Weitzel JN | Archives of surgery (Chicago, Ill. : 1960) | 2003 | PMID: 14662532 |
BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. | Basham VM | Breast cancer research : BCR | 2002 | PMID: 11879560 |
Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. | Anglian Breast Cancer Study Group | British journal of cancer | 2000 | PMID: 11044354 |
Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. | Gayther SA | Nature genetics | 1997 | PMID: 8988179 |
The cultural reasons underlying this meeting. | Manuali C | History and philosophy of the life sciences | 1988 | PMID: 3413277 |
Room air ventilation for total intravenous general anaesthesia. | Cardan E | Annales francaises d'anesthesie et de reanimation | 1988 | PMID: 3146935 |
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Text-mined citations for rs80359343 ...
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.