ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7786G>A (p.Gly2596Arg)
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.
Likely pathogenic(2); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7786G>A (p.Gly2596Arg)
Variation ID: 91492 Accession: VCV000091492.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32357910 (GRCh38) [ NCBI UCSC ] 13: 32932047 (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 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7786G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Gly2596Arg missense NC_000013.11:g.32357910G>A NC_000013.10:g.32932047G>A NG_012772.3:g.47431G>A LRG_293:g.47431G>A LRG_293t1:c.7786G>A LRG_293p1:p.Gly2596Arg - Protein change
- G2596R
- Other names
- p.G2596R:GGA>AGA
- 8014G>A
- Canonical SPDI
- NC_000013.11:32357909: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 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
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 |
18726 | 18884 |
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 (3) |
criteria provided, single submitter
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Aug 2, 2016 | RCV000077009.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 4, 2020 | RCV000160142.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 16, 2024 | RCV000197789.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 27, 2023 | RCV000509715.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 12, 2017 | RCV000770731.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 21, 2023 | RCV003460727.1 |
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
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 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000902212.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Uncertain significance
(Jun 05, 2019)
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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: SCV000683904.3
First in ClinVar: Feb 19, 2018 Last updated: Jun 22, 2020 |
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Uncertain significance
(Jan 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: SCV000296520.2
First in ClinVar: Sep 27, 2014 Last updated: Jan 26, 2021 |
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Uncertain significance
(Mar 04, 2020)
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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: SCV000210447.12
First in ClinVar: Feb 24, 2015 Last updated: May 29, 2016 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8014G>A; Published functional studies demonstrate impaired homology directed repair activity (Guidugli 2018, Hart 2018); This variant is associated with the following publications: (PMID: 29394989, 30254663, 29884841) (less)
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Uncertain significance
(Aug 02, 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: SCV000489011.2
First in ClinVar: Sep 27, 2014 Last updated: Dec 24, 2022 |
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Uncertain significance
(Jul 21, 2023)
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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: SCV004216004.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Apr 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623182.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: BRCA2 c.7786G>A (p.Gly2596Arg) results in a non-conservative amino acid change located in the breast cancer type 2 susceptibility protein, helical domain (IPR015252) of … (more)
Variant summary: BRCA2 c.7786G>A (p.Gly2596Arg) results in a non-conservative amino acid change located in the breast cancer type 2 susceptibility protein, helical domain (IPR015252) of 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 251378 control chromosomes. c.7786G>A has been reported in the literature as a VUS in at-least one individual affected with male breast cancer (Rizzolo_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal homology directed repair (HDR) activity and a non-functional impact using a well-established mouse embryonic stem cell based assay (example, Biswas_2020, Guidugli_2018). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6). At-least one submitter reports a likely pathogenic classiciation using overlapping functional evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Jan 16, 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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Invitae
Accession: SCV000254212.9
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2596 of the BRCA2 protein (p.Gly2596Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2596 of the BRCA2 protein (p.Gly2596Arg). This variant is present in population databases (rs398122591, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333, 30613976). ClinVar contains an entry for this variant (Variation ID: 91492). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 29884841, 33293522). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 pathogenic
(Jun 27, 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: SCV000608032.6
First in ClinVar: Oct 23, 2017 Last updated: May 01, 2024 |
Comment:
The p.G2596R variant (also known as c.7786G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide … (more)
The p.G2596R variant (also known as c.7786G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7786. The glycine at codon 2596 is replaced by arginine, an amino acid with dissimilar properties. Three separate homology-directed DNA repair (HDR) assays have demonstrated p.G2596R is non-functional (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248; Hart SN et al. Genet. Med., 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). Another alteration at the same codon, p.G2596E (c.7787G>A), has been described as having low functionality in a HDR assay (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Uncertain significance
(Mar 23, 2010)
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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: SCV000108806.2
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
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Uncertain significance
(Sep 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228443.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
PS3(Strong)+PM2(Supporting)+PP3(Supporting)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
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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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Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance. | Richardson ME | American journal of human genetics | 2021 | PMID: 33609447 |
A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays. | Biswas K | NPJ genomic medicine | 2020 | PMID: 33293522 |
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. | Rizzolo P | International journal of cancer | 2019 | PMID: 30613976 |
Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help? | Zuntini R | Frontiers in genetics | 2018 | PMID: 30254663 |
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. | Guidugli L | American journal of human genetics | 2018 | PMID: 29394989 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Text-mined citations for rs398122591 ...
HelpRecord last updated May 01, 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.