ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8042C>G (p.Thr2681Arg)
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(11); 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.8042C>G (p.Thr2681Arg)
Variation ID: 142520 Accession: VCV000142520.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32363244 (GRCh38) [ NCBI UCSC ] 13: 32937381 (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 Aug 1, 2016 Jun 17, 2024 Feb 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8042C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Thr2681Arg missense NC_000013.11:g.32363244C>G NC_000013.10:g.32937381C>G NG_012772.3:g.52765C>G LRG_293:g.52765C>G LRG_293t1:c.8042C>G LRG_293p1:p.Thr2681Arg - Protein change
- T2681R
- Other names
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- Canonical SPDI
- NC_000013.11:32363243:C: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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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, multiple submitters, no conflicts
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Nov 30, 2023 | RCV000131690.21 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV000168172.22 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000239323.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 30, 2023 | RCV000781102.12 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 22, 2023 | RCV000724545.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 14, 2017 | RCV001114096.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 29, 2024 | RCV003462020.2 |
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
(Jul 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296671.3
First in ClinVar: Aug 01, 2016 Last updated: Jan 03, 2022 |
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Uncertain significance
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279383.10
First in ClinVar: May 29, 2016 Last updated: Jun 03, 2023 |
Comment:
Published functional studies suggest no impact on function: performed similar to wild type in cell survival and drug-sensitivity assays (Biswas et al., 2020); Observed in … (more)
Published functional studies suggest no impact on function: performed similar to wild type in cell survival and drug-sensitivity assays (Biswas et al., 2020); Observed in individuals with a personal or family history including breast and/or ovarian cancer (Lu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8270C>G; This variant is associated with the following publications: (PMID: 18951461, 18824701, 28339459, 29884841, 31853058, 32377563, 31131967, 12228710, 22476429, 33293522) (less)
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Uncertain significance
(Feb 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213595.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Apr 13, 2018)
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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: SCV000786342.2
First in ClinVar: Aug 01, 2016 Last updated: Aug 01, 2016 |
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Uncertain significance
(Jan 09, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000226715.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Sex: mixed
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Uncertain significance
(Oct 14, 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
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Illumina Laboratory Services, Illumina
Accession: SCV001271927.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Oct 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group D1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001271928.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(May 30, 2023)
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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: SCV000918933.4
First in ClinVar: Jun 02, 2019 Last updated: Jun 24, 2023 |
Comment:
Variant summary: BRCA2 c.8042C>G (p.Thr2681Arg) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five … (more)
Variant summary: BRCA2 c.8042C>G (p.Thr2681Arg) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251192 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8042C>G has been reported in the literature in individuals affected with breast cancer (example, Spearman_2008, Lu_2012), but has also been reported at a carrier frequency of 0.0001365 in a cohort of European American women over the age of 70 with no history of cancer (FLOSSIES dataset). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been observed at our laboratory (CHEK2 c.283C>T, p.Arg95X; BRCA2 c.1755_1759delGAAAA, p.Lys585AsnfsX3), providing supporting evidence for a benign role. One study showed that this variant has a weak impact on splicing, with the canonical transcript at approximately 97.7% (Fraile-Bethencourt_BRCA2_PLOS_2017). Additionally, one functional study showed no damaging effect of this variant by cell survival and drug sensitivity (Biswas_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 28339459, 22476429, 18824701). Eight ClinVar submitters have assessed this variant since 2014: seven classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Nov 30, 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: SCV000689092.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with arginine at codon 2681 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with arginine at codon 2681 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 in mouse embryonic stem cells showed that this variant did not impact cell viability or drug sensitivity (PMID: 33293522). This variant has been reported in individuals with a personal or family history of breast or ovarian cancer (PMID: 18824701, 22476429) and in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.690, 1.102 and 0.858, respectively (PMID: 31131967). This variant has not been identified 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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Likely benign
(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: SCV000218834.12
First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024 |
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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: SCV004845593.1
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 arginine at codon 2681 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with arginine at codon 2681 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 in mouse embryonic stem cells showed that this variant did not impact cell viability or drug sensitivity (PMID: 33293522). This variant has been reported in individuals with a personal or family history of breast or ovarian cancer (PMID: 18824701, 22476429) and in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.690, 1.102 and 0.858, respectively (PMID: 31131967). This variant has not been identified 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: 1
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Uncertain significance
(Mar 03, 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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Ambry Genetics
Accession: SCV000186726.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T2681R variant (also known as c.8042C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide … (more)
The p.T2681R variant (also known as c.8042C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8042. The threonine at codon 2681 is replaced by arginine, an amino acid with similar properties. In another study, this variant was seen in 1/146 patients with breast cancer from high risk families, with at least two first- and second-degree relatives diagnosed with breast and/or ovarian cancer (Lu W et al. Fam. Cancer. 2012 Sep;11(3):381-5). A study utilizing a splicing reporter minigene assay found this alteration to have a weak impact on splicing (Fraile-Bethencourt E et al. PLoS Genet., 2017 Mar;13:e1006691). This variant was found to be functional in a mouse embryonic stem cell complementation and drug sensitivity assay (Biswas K et al. NPJ Genom Med 2020 Dec;5(1):52). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays. | Biswas K | NPJ genomic medicine | 2020 | PMID: 33293522 |
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18. | Fraile-Bethencourt E | PLoS genetics | 2017 | PMID: 28339459 |
Mutation screening of RAD51C in high-risk breast and ovarian cancer families. | Lu W | Familial cancer | 2012 | PMID: 22476429 |
Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. | Spearman AD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18824701 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 | - | - | - | - |
Text-mined citations for rs587782519 ...
HelpRecord last updated Oct 13, 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.