ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.9098C>T (p.Thr3033Ile)
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.
Uncertain significance(7); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.9098C>T (p.Thr3033Ile)
Variation ID: 96879 Accession: VCV000096879.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32379894 (GRCh38) [ NCBI UCSC ] 13: 32954031 (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 May 1, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.9098C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Thr3033Ile missense NC_000013.11:g.32379894C>T NC_000013.10:g.32954031C>T NG_012772.3:g.69415C>T LRG_293:g.69415C>T LRG_293t1:c.9098C>T LRG_293p1:p.Thr3033Ile - Protein change
- T3033I
- Other names
- 9326C>T
- Canonical SPDI
- NC_000013.11:32379893:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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
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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
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 |
18951 | 19110 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, single submitter
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Jan 11, 2024 | RCV000083000.5 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 25, 2023 | RCV000166290.16 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 14, 2020 | RCV000269121.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV000689164.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 20, 2022 | RCV001824601.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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
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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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Uncertain significance
(Jun 01, 2018)
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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: SCV000329146.7
First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted BRCA2 c.9098C>T at the cDNA level, p.Thr3033Ile (T3033I) at the protein level, and results in the change of a Threonine to … (more)
This variant is denoted BRCA2 c.9098C>T at the cDNA level, p.Thr3033Ile (T3033I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 9326C>T. This variant has been reported in individuals with personal and/or family history of breast cancer and ovarian cancer, and exhibited an intermediate level of homology-directed repair (HDR) activity in a cell-based functional assay (Guidugli 2013, Eccles 2015, Couch 2015, Guidugli 2018). BRCA2 Thr3033Ile was not observed in large population cohorts (Lek 2016). BRCA2 Thr3033Ile is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Thr3033Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Jan 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074358.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: BRCA2 c.9098C>T (p.Thr3033Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: BRCA2 c.9098C>T (p.Thr3033Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249408 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9098C>T has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer (examples: Couch_2015 and Eccles_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. This variant was described as likely neutral using HDR assay (Guidugli_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and described the variant as likely benign (n=1) and as a variant of uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Oct 14, 2020)
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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: SCV002046116.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000004 (1/249408 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000004 (1/249408 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 26153499 (2015), 25452441 (2015), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). Additionally, functional studies report inconclusive results regarding the variant’s effects on repair activity (PMIDs: 29394989 (2018), 24323938 (2014), and 23108138 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Oct 25, 2023)
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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: SCV000684023.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with isoleucine at codon 3033 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with isoleucine at codon 3033 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function in a homology-directed repair assay (PMID: 29394989). This variant has been reported in at least three individuals affected with breast and/or ovarian cancer (PMID: 25452441, 26153499, 33471991; Leiden Open Variation Database DB-ID BRCA2_007511). This variant has been identified in 1/249408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Jan 11, 2024)
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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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All of Us Research Program, National Institutes of Health
Accession: SCV004846121.1
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 missense variant replaces threonine with isoleucine at codon 3033 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with isoleucine at codon 3033 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function in a homology-directed repair assay (PMID: 29394989). This variant has been reported in at least three individuals affected with breast and/or ovarian cancer (PMID: 25452441, 26153499, 33471991; Leiden Open Variation Database DB-ID BRCA2_007511). This variant has been identified in 1/249408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Feb 18, 2022)
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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: SCV002532005.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.9098C>T (p.T3033I) variant has been reported in heterozygosity in at least four individuals with hereditary breast and/or ovarian cancer (PMID: 33471991, 25452441, 26153499). … (more)
The BRCA2 c.9098C>T (p.T3033I) variant has been reported in heterozygosity in at least four individuals with hereditary breast and/or ovarian cancer (PMID: 33471991, 25452441, 26153499). Functional studies indicate that this variant does not significantly alter homology directed repair activity (PMID: 23108138, 24323938, 29394989). In silico predictions of the variant's effect on protein function are inconclusive. This variant was observed in 1/249408 chromosomes across the different populations included in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 96879). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jan 02, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000816804.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3033 of the BRCA2 protein (p.Thr3033Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3033 of the BRCA2 protein (p.Thr3033Ile). 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 missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25452441, 26153499). ClinVar contains an entry for this variant (Variation ID: 96879). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 23108138, 24323938, 29394989). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Mar 04, 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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Ambry Genetics
Accession: SCV000217073.6
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Apr 08, 2009)
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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: SCV000115074.2
First in ClinVar: Feb 09, 2014 Last updated: Sep 27, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. | Guidugli L | American journal of human genetics | 2018 | PMID: 29394989 |
BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. | Eccles DM | Annals of oncology : official journal of the European Society for Medical Oncology | 2015 | PMID: 26153499 |
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. | Couch FJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25452441 |
Functional assays for analysis of variants of uncertain significance in BRCA2. | Guidugli L | Human mutation | 2014 | PMID: 24323938 |
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. | Guidugli L | Cancer research | 2013 | PMID: 23108138 |
Text-mined citations for rs431825374 ...
HelpRecord last updated Sep 29, 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.