ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8902A>G (p.Thr2968Ala)
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.8902A>G (p.Thr2968Ala)
Variation ID: 141798 Accession: VCV000141798.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32379464 (GRCh38) [ NCBI UCSC ] 13: 32953601 (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 Jul 24, 2016 Sep 16, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8902A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Thr2968Ala missense NC_000013.11:g.32379464A>G NC_000013.10:g.32953601A>G NG_012772.3:g.68985A>G LRG_293:g.68985A>G LRG_293t1:c.8902A>G LRG_293p1:p.Thr2968Ala - Protein change
- T2968A
- Other names
- p.T2968A:ACC>GCC
- Canonical SPDI
- NC_000013.11:32379463:A:G
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
18955 | 19114 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV000130450.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 31, 2024 | RCV000160160.11 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000410479.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV000557418.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2022 | RCV000588120.9 |
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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Uncertain significance
(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: SCV001139237.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Nov 16, 2021)
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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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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512308.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PM2 moderate, BP4 supporting
Geographic origin: Brazil
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Uncertain significance
(Oct 27, 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: SCV002531984.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.8902A>G (p.T2968A) variant has been reported in individuals with breast cancer or prostate cancer (PMIDs 26976419, 29659569). It is reported in a large … (more)
The BRCA2 c.8902A>G (p.T2968A) variant has been reported in individuals with breast cancer or prostate cancer (PMIDs 26976419, 29659569). It is reported in a large breast cancer case control study in 1/60,466 women with breast cancer and 2/53,461 controls (PMID 33471991). This variant was observed in 2/35226 chromosomes in the Latino population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 141798). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
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Uncertain significance
(Sep 09, 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: SCV000185314.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T2968A variant (also known as c.8902A>G), located in coding exon 21 of the BRCA2 gene, results from an A to G substitution at nucleotide … (more)
The p.T2968A variant (also known as c.8902A>G), located in coding exon 21 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8902. The threonine at codon 2968 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). In addition, this variant was identified as a germline alteration in 1/135 ovarian cancer patients screened for BRCA1/2 (Peixoto A et al. Front Oncol. 2020 Jul;10:1318). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Dec 16, 2022)
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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: SCV000210487.15
First in ClinVar: Feb 24, 2015 Last updated: Dec 24, 2022 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9130A>G; This variant is associated with the following publications: … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9130A>G; This variant is associated with the following publications: (PMID: 25348012, 26976419, 16683254, 29659569, 12228710, 29884841, 33471991, 32850417, 32377563) (less)
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Uncertain significance
(Dec 10, 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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Counsyl
Accession: SCV000487987.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Jan 13, 2022)
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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: SCV000600829.5
First in ClinVar: Jul 24, 2016 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000011 (3/281158 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, 0.000011 (3/281158 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 cancer (PMID: 26976419 (2016)), prostate cancer (PMID: 29659569 (2018)), and ovarian cancer (PMID: 32850417 (2020)). In a large breast cancer association study, this variant was reported in individuals affected with breast cancer as well as unaffected individuals (PMID: 33471991 (2021)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jul 17, 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: SCV000903030.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with alanine at codon 2968 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with alanine at codon 2968 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual each affected with breast, ovarian, or prostate cancer (PMID: 26976419, 29659569, 32850417; Color internal data). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001114). This variant has been identified in 3/281158 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
(Dec 11, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000635698.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2968 of the BRCA2 protein (p.Thr2968Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2968 of the BRCA2 protein (p.Thr2968Ala). This variant is present in population databases (rs587782021, gnomAD 0.006%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 26976419, 32850417). ClinVar contains an entry for this variant (Variation ID: 141798). 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%. 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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Uncertain Significance
(Dec 18, 2023)
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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: SCV004846088.1
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 alanine at codon 2968 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with alanine at codon 2968 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual each affected with breast, ovarian, or prostate cancer (PMID: 26976419, 29659569, 32850417; Color internal data). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001114). This variant has been identified in 3/281158 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
(Jul 31, 2024)
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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: SCV000695189.6
First in ClinVar: Mar 17, 2018 Last updated: Sep 16, 2024 |
Comment:
Variant summary: BRCA2 c.8902A>G (p.Thr2968Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.8902A>G (p.Thr2968Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249760 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8902A>G has been identified in individuals with lung cancer (e.g. Heeke_2020), ovarian cancer (Peixoto_2020) and in settings of multigene panel testing among individuals with breast cancer (e.g., Tung_2015) and prostate cancer (e.g., Paulo_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16683254, 25348012, 26976419, 29659569, 32377563, 32850417, 32066459). ClinVar contains an entry for this variant (Variation ID: 141798). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Tumor Testing for Somatic and Germline BRCA1/BRCA2 Variants in Ovarian Cancer Patients in the Context of Strong Founder Effects. | Peixoto A | Frontiers in oncology | 2020 | PMID: 32850417 |
Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML. | Hart SN | NPJ breast cancer | 2020 | PMID: 32377563 |
Prospective evaluation of NGS-based liquid biopsy in untreated late stage non-squamous lung carcinoma in a single institution. | Heeke S | Journal of translational medicine | 2020 | PMID: 32066459 |
Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer. | Paulo P | PLoS genetics | 2018 | PMID: 29659569 |
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
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 |
Text-mined citations for rs587782021 ...
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.