ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)
Variation ID: 38215 Accession: VCV000038215.76
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32379913 (GRCh38) [ NCBI UCSC ] 13: 32954050 (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 Jun 17, 2024 Jun 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.9117G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Pro3039= synonymous NC_000013.11:g.32379913G>A NC_000013.10:g.32954050G>A NG_012772.3:g.69434G>A LRG_293:g.69434G>A LRG_293t1:c.9117G>A LRG_293p1:p.Pro3039= U43746.1:n.9345G>A - Protein change
- Other names
- P3039P
- p.P3039P:CCG>CCA
- NM_000059.4(BRCA2):c.9117G>A
- p.Pro3039=
- 9345G>A
- Canonical SPDI
- NC_000013.11:32379912: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
18935 | 19094 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (14) |
reviewed by expert panel
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Nov 9, 2023 | RCV000031798.30 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000045725.31 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000074560.31 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 19, 2023 | RCV000131039.19 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515207.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763330.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2020 | RCV001310189.9 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2019 | RCV001171453.11 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 9, 2021 | RCV001554310.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV003473227.2 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162286.8 | |
Pathogenic (1) |
reviewed by expert panel
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Jun 11, 2024 | RCV004566785.1 | |
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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
Help
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
(Jun 11, 2024)
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reviewed by expert panel
Method: curation
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BRCA2-related cancer predisposition
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004101443.3 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024 |
Comment:
The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer … (more)
The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by exon skipping (PMIDs: 17011978, 23451180, 22505045, 31843900, 32398771, 22632462). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3364.725 (based on Co-occurrence LR=2.231; Family History LR=1508.137), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very Strong met; PMID: 17924331, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_VeryStrong). (less)
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Pathogenic
(Sep 18, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000575743.1
First in ClinVar: May 07, 2017 Last updated: May 07, 2017 |
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Pathogenic
(Oct 10, 2014)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743359.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Pathogenic
(May 28, 2019)
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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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Mendelics
Accession: SCV001139248.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Nov 03, 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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450340.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 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: yes
Allele origin:
germline
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Department of Medical Genetics, Oslo University Hospital
Accession: SCV000605690.3
First in ClinVar: Sep 28, 2017 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 5
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Pathogenic
(Aug 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296758.6
First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024 |
Comment:
It has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 10638982 (2000), 17011978 (2006), 17924331 (2007), 22505045 (2012), … (more)
It has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 10638982 (2000), 17011978 (2006), 17924331 (2007), 22505045 (2012), 21990134 (2012), 23451180 (2013), 28724667 (2017)). Furthermore, experimental studies have shown that the variant causes the skipping of exon 23, resulting in premature termination in protein synthesis (PMID: 22505045 (2012), 22632462 (2012), 23451180 (2013), and 27060066 (2016)). Based on the available information, the variant is classified as pathogenic. (less)
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Pathogenic
(Jun 30, 2022)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848273.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Pro3039Pro (c.9117G>A) variant in BRCA2 has been reported in at least 16 individuals with BRCA2-related cancer (Peelen 2000 PMID: 10638982, Houdayer 2012 PMID: 22505045, … (more)
The p.Pro3039Pro (c.9117G>A) variant in BRCA2 has been reported in at least 16 individuals with BRCA2-related cancer (Peelen 2000 PMID: 10638982, Houdayer 2012 PMID: 22505045, Willems-Jones 2012 PMID: 23035815, de Juan 2015 PMID: 26026974, Corman 2016 PMID: 27000661, Labidi-Galy 2018 PMID: 29084914). It has also been identified in 1/111660 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant has also been identified in ClinVar (Variation ID: 38215). This variant is located in the last base of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, and both in vitro studies and testing of patient RNA have shown that this variant results in exon skipping, which is predicted to lead to an absent or truncated protein (Peelen 2000 PMID: 10638982, Acedo 2012 PMID: 22632462, Houdayer 2012 PMID: 22505045, Colombo 2013 PMID: 23451180). Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Another variant, c.9117G>T, resulting in the same synonymous change and predicted splicing impact has also been identified in individuals with BRCA2-related cancers. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS3, PM2, PS4. (less)
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Pathogenic
(Apr 08, 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: SCV000185969.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.9117G>A pathogenic mutation (also known as p.P3039P), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at … (more)
The c.9117G>A pathogenic mutation (also known as p.P3039P), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9117. This nucleotide substitution does not change the at codon 3039. However, this change occurs in the last base pair of coding exon 22 and has been shown to cause aberrant RNA transcripts due to exon skipping that results in a frameshift at codon 2985 and premature protein truncation (V2985Gfs*3) (Ambry internal data; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Acedo A et al. Hum. Mutat. 2015 Feb;36:210-21). This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Hamann U et al. J. Med. Genet. 2002 Mar;39:E12; Spurdle AB et al. J. Clin. Oncol. 2008 Apr;26:1657-63; Fong PC et al. J. Clin. Oncol. 2010 May;28:2512-9; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Takahashi M et al. Breast Cancer. 2017 Mar;24(2):336-340; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). This alteration has also been reported in a male with aggressive prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6) and in biological males with breast cancer (de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Corman V et al. Endocr. Relat. Cancer. 2016 May;23:391-7). Of note, this mutation is also designated as 9345G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 21, 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: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744555.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Pathogenic
(May 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:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839919.1
First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
Comment:
The c.9117G>A (p.Pro3039Pro) variant in the BRCA2 gene has been detected in multiple patients and families with breast and/or ovarian cancer [PMID 10638982 reported as … (more)
The c.9117G>A (p.Pro3039Pro) variant in the BRCA2 gene has been detected in multiple patients and families with breast and/or ovarian cancer [PMID 10638982 reported as 3398delAAAAG, 27000661] and a cohort of patients with prostate cancer [PMID 23035815, reported as c.9117 G>A (p.Val2985fs)]. The nucleotide position 9117 is the last nucleotide of exon 23. Several in vitro assays showed that the change leads aberrant splicing and the skipping of exon 23 [PMID 22505045, 23451180]. This variant is thus predicted to result in a loss of function of the protein. This variant has not been reported in the ExAC database. This variant thus classified as pathogenic. (less)
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Pathogenic
(Feb 03, 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: SCV000488254.2
First in ClinVar: Sep 27, 2014 Last updated: Dec 24, 2022 |
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Pathogenic
(Sep 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021530.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211922.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(May 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Familial prostate cancer Tracheoesophageal fistula Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611181.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894007.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(May 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251960.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
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Pathogenic
(Oct 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000494420.2
First in ClinVar: Feb 04, 2017 Last updated: Nov 11, 2020 |
Comment:
Variant summary: BRCA2 c.9117G>A (p.Pro3039Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a … (more)
Variant summary: BRCA2 c.9117G>A (p.Pro3039Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict that the variant abolishes a 5' splicing donor site. Multiple publications report experimental evidence that this variant affects mRNA splicing (e.g. Bonatti_2006, Acedo_2012, Houdayer_2012, Colombo_2013). The variant allele was found at a frequency of 4e-06 in 248378 control chromosomes. c.9117G>A has been reported in the literature in many individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Peelen_2000, Meindl_2002, Bonatti_2006, Novakovic_2012, Nakamura_2013, Corman_2016, Barrios_2017). These data indicate that the variant is very likely to be associated with disease. 17 other ClinVar submitters, including an 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
(Jul 01, 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
|
Sema4, Sema4
Accession: SCV002532009.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.9117G>A (p.P3039=) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancers (PMID: 25186627, 28477318, 28724667, 28825054, 29176636, … (more)
The BRCA2 c.9117G>A (p.P3039=) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancers (PMID: 25186627, 28477318, 28724667, 28825054, 29176636, 32393398). This variant is also known as 9345G>A in the literature.Functional studies have shown that this variant alters splicing leading to a skipping of exon 23 and creation of a premature stop codon at amino acid 2985 (PMID: 10638982, 17011978, 23451180 ). At this location, this is predicted to result in absent protein (loss of function). Loss of function variants in BRCA2 are known to be pathogenic (PMID: 29446198). This variant was observed in 1/111660 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 38215). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000108645.18
First in ClinVar: Dec 10, 2013 Last updated: Mar 04, 2023 |
Comment:
Observed in multiple breast/ovarian cancer families (Peelan 2000, Risch 2006, Novakovic 2012, Tea 2014, de Juan 2015, Gabald Barrios 2017, Sun 2017); Multifactorial studies suggest … (more)
Observed in multiple breast/ovarian cancer families (Peelan 2000, Risch 2006, Novakovic 2012, Tea 2014, de Juan 2015, Gabald Barrios 2017, Sun 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Lindor 2012); Published functional studies demonstrate a damaging effect: disruption of a splice donor site which causes aberrant RNA processing, specifically skipping of exon 23, and predicted to result in protein truncation (Peelen 2000, Bonatti 2006, Acedo 2012, Colombo 2013); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 9345G>A; This variant is associated with the following publications: (PMID: 22798144, 17011978, 22505045, 22632462, 26026974, 25948282, 28477318, 29084914, 31447099, 32398771, 32658311, 17924331, 23451180, 23035815, 22923021, 17148771, 20507642, 22217648, 18375895, 10638982, 9133456, 21324516, 18821011, 25556971, 28008555, 24156927, 27000661, 21702907, 28740454, 28873162, 27271530, 25186627, 28724667, 25382762, 29805665, 29907814, 29339979, 28825054, 30702160, 31957001, 31143373, 29176636, 21990134, 31825140, 32853339, 30787465) (less)
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Pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004027489.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Pathogenic
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537643.3
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA … (more)
This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA studies have shown that this variant impacts splicing resulting in exon 23 skipping and introducing premature stop (PMID: 22505045, 23451180, 25382762, 27060066, 31843900, 32393398). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast or ovarian cancer (PMID: 18821011, 22798144, 24156927, 24249303, 25480878, 25556971, 25948282, 26026974, 27000661, 28477318, 28724667, 30287823). This variant has been identified in 1/248378 chromosomes 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 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000073738.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with breast, ovarian, or prostate cancer (PMID: 10638982, 17011978, 17148771, 22923021, 23035815, 26026974). This variant is also known as 9345G>A. ClinVar contains an entry for this variant (Variation ID: 38215). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23 and introduces a premature termination codon (PMID: 22505045, 22632462, 23035815, 23451180, 25382762; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004846127.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA … (more)
This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA studies have shown that this variant impacts splicing resulting in exon 23 skipping and introducing premature stop (PMID: 22505045, 23451180, 25382762, 27060066, 31843900, 32393398). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast or ovarian cancer (PMID: 18821011, 22798144, 24156927, 24249303, 25480878, 25556971, 25948282, 26026974, 27000661, 28477318, 28724667, 30287823). This variant has been identified in 1/248378 chromosomes 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)
Number of individuals with the variant: 4
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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499784.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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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
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000328057.4
First in ClinVar: Sep 27, 2014 Last updated: Dec 11, 2022 |
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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
|
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587988.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(Aug 09, 2021)
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no assertion criteria provided
Method: clinical testing
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Breast carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001774869.1
First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021 |
Comment:
Diagnosis: Breast cancer Pathology: Invasive ductal breast carcinoma IHC: ER:+, PR:+, HER2:-
Age: 40-49 years
Sex: female
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Pathogenic
(Aug 31, 2013)
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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: SCV000054406.5
First in ClinVar: Apr 04, 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
|
Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147546.2
First in ClinVar: Apr 01, 2014 Last updated: Sep 27, 2014 |
Observation 1:
Number of individuals with the variant: 4
Observation 2:
Number of individuals with the variant: 2
Ethnicity/Population group: African
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
Observation 5:
Number of individuals with the variant: 4
Ethnicity/Population group: Western European
Observation 6:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Italian
Observation 7:
Number of individuals with the variant: 1
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Pathogenic
(Sep 01, 2019)
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no assertion criteria provided
Method: research
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Hereditary breast and ovarian cancer syndrome
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
|
King Laboratory, University of Washington
Accession: SCV001251364.1
First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Comment:
Transcript analysis by cBROCA
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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:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955049.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758412.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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Pathogenic
(-)
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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
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733331.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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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:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906367.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
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Pathogenic
(Aug 26, 2022)
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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
|
BRCAlab, Lund University
Accession: SCV002588935.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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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 |
---|---|---|---|---|
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer. | Darst BF | Journal of the National Cancer Institute | 2021 | PMID: 32853339 |
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay. | Sirisena N | Breast cancer research : BCR | 2020 | PMID: 32393398 |
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients. | Gao X | Human mutation | 2020 | PMID: 31825140 |
Characterization of splice-altering mutations in inherited predisposition to cancer. | Casadei S | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31843900 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Analysis of clinical characteristics of breast cancer patients with the Japanese founder mutation BRCA1 L63X. | Yoshida R | Oncotarget | 2019 | PMID: 31143373 |
Toward automation of germline variant curation in clinical cancer genetics. | Ravichandran V | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30787465 |
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients. | Bhaskaran SP | International journal of cancer | 2019 | PMID: 30702160 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
The germline mutational landscape of BRCA1 and BRCA2 in Brazil. | Palmero EI | Scientific reports | 2018 | PMID: 29907814 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan. | Arai M | Journal of human genetics | 2018 | PMID: 29176636 |
Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. | Labidi-Galy SI | Clinical cancer research : an official journal of the American Association for Cancer Research | 2018 | PMID: 29084914 |
Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. | Abida W | JCO precision oncology | 2017 | PMID: 28825054 |
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. | Sun J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28724667 |
Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers. | Gabaldó Barrios X | Familial cancer | 2017 | PMID: 28477318 |
OLA1 gene sequencing in patients with BRCA1/2 mutation-negative suspected hereditary breast and ovarian cancer. | Takahashi M | Breast cancer (Tokyo, Japan) | 2017 | PMID: 27271530 |
Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples. | Fackenthal JD | Journal of medical genetics | 2016 | PMID: 27060066 |
Breast cancer in a male-to-female transsexual patient with a BRCA2 mutation. | Corman V | Endocrine-related cancer | 2016 | PMID: 27000661 |
BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. | de Juan I | Familial cancer | 2015 | PMID: 26026974 |
New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. | Kluska A | BMC medical genomics | 2015 | PMID: 25948282 |
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 |
Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer. | Wang C | Annals of oncology : official journal of the European Society for Medical Oncology | 2015 | PMID: 25480878 |
Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. | Acedo A | Human mutation | 2015 | PMID: 25382762 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Prevalence and differentiation of hereditary breast and ovarian cancers in Japan. | Nakamura S | Breast cancer (Tokyo, Japan) | 2015 | PMID: 24249303 |
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. | Tea MK | Maturitas | 2014 | PMID: 24156927 |
Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. | Colombo M | PloS one | 2013 | PMID: 23451180 |
High grade prostatic intraepithelial neoplasia does not display loss of heterozygosity at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer. | Willems-Jones A | BJU international | 2012 | PMID: 23035815 |
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families. | Novaković S | International journal of oncology | 2012 | PMID: 22923021 |
Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. | Kim H | Breast cancer research and treatment | 2012 | PMID: 22798144 |
Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes. | Acedo A | Breast cancer research : BCR | 2012 | PMID: 22632462 |
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. | Houdayer C | Human mutation | 2012 | PMID: 22505045 |
Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: the importance of whole-gene sequencing. | Jang JH | Journal of human genetics | 2012 | PMID: 22217648 |
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. | Zhang S | Gynecologic oncology | 2011 | PMID: 21324516 |
Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. | Fong PC | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2010 | PMID: 20406929 |
Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation. | Seong MW | Clinical genetics | 2009 | PMID: 19656164 |
Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. | Papi L | Breast cancer research and treatment | 2009 | PMID: 18821011 |
Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer. | Sugano K | Cancer science | 2008 | PMID: 19016756 |
Clinical classification of BRCA1 and BRCA2 DNA sequence variants: the value of cytokeratin profiles and evolutionary analysis--a report from the kConFab Investigators. | Spurdle AB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18375895 |
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. | Risch HA | Journal of the National Cancer Institute | 2006 | PMID: 17148771 |
RNA-based analysis of BRCA1 and BRCA2 gene alterations. | Bonatti F | Cancer genetics and cytogenetics | 2006 | PMID: 17011978 |
A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. | van der Hout AH | Human mutation | 2006 | PMID: 16683254 |
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. | Hamann U | Journal of medical genetics | 2002 | PMID: 11897832 |
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. | Meindl A | International journal of cancer | 2002 | PMID: 11802209 |
Screening for BRCA2 mutations in 81 Dutch breast-ovarian cancer families. | Peelen T | British journal of cancer | 2000 | PMID: 10638982 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7f116122-06ef-40a9-934f-9c6654fe75f9 | - | - | - | - |
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Text-mined citations for rs28897756 ...
HelpRecord last updated Aug 25, 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.