ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.8009C>G (p.Ser2670Trp)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(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.8009C>G (p.Ser2670Trp)
Variation ID: 489785 Accession: VCV000489785.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32363211 (GRCh38) [ NCBI UCSC ] 13: 32937348 (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 Feb 19, 2018 Oct 8, 2024 Apr 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.8009C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Ser2670Trp missense NC_000013.11:g.32363211C>G NC_000013.10:g.32937348C>G NG_012772.3:g.52732C>G LRG_293:g.52732C>G LRG_293t1:c.8009C>G LRG_293p1:p.Ser2670Trp - Protein change
- S2670W
- Other names
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- Canonical SPDI
- NC_000013.11:32363210: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.
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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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 16, 2023 | RCV000579856.7 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 9, 2024 | RCV001212985.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 1, 2024 | RCV003886416.7 |
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
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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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Pathogenic
(Aug 04, 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: SCV001384598.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser2670 amino acid residue in BRCA2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser2670 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19043619, 23096355, 24735155, 26250392, 29394989). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 28339459). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 34597585). ClinVar contains an entry for this variant (Variation ID: 489785). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 28664449, 29752822). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 2670 of the BRCA2 protein (p.Ser2670Trp). (less)
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Likely pathogenic
(Jun 10, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683934.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with tryptophan at codon 2670 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces serine with tryptophan at codon 2670 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An RNA study reported that this variant caused leaky out-of-frame skipping of exon 18 in a minigene splicing assay (PMID: 28339459). This variant has been reported in an individual affected with breast cancer and several suspected hereditary breast and ovarian cancer families (PMID: 28664449, 29752822, 34597585). This variant has been observed to cosegregate with disease in multiple families with a likelihood ratio for pathogenicity of 819.97 (PMID: 34597585). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Nov 16, 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: SCV005030332.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The p.S2670W variant (also known as c.8009C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide … (more)
The p.S2670W variant (also known as c.8009C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8009. The serine at codon 2670 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved through mammals but not in all available vertebrate species. RNA studies have shown this variant to result in an incomplete splicing impact, resulting in a transcript which skips exon 17 that is expected to result in loss-of-function (Ambry internal data; Fraile-Bethencourt E et al. Front Genet, 2019 May;10:503; Fraile-Bethencourt E et al. PLoS Genet, 2017 Mar;13:e1006691). This alteration was classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, and tumor pathology data (Caputo SM et al. Am J Hum Genet, 2021 Oct;108:1907-1923). This variant was deleterious in a drug sensitivity protein functional assay (Ikegami M et al. Nat Commun, 2020 May;11:2573). Based on internal structural analysis, S2670W is structurally deleterious. The variant is highly destabilizing to the local structure (Yang H et al. Science, 2002 Sep;297:1837-48) In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Apr 09, 2024)
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criteria provided, single submitter
Method: curation
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Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV005184350.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls, PP4 (very strong pathogenic): Caputo SM et … (more)
According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls, PP4 (very strong pathogenic): Caputo SM et al., 2021, Combined LR: 7,283.30 , BP4 (supporting benign): BayesDel no-AF score: 0.1593 (less)
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Uncertain significance
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004703689.7
First in ClinVar: Mar 10, 2024 Last updated: Oct 08, 2024 |
Comment:
BRCA2: PM2, PM5, PS4:Moderate, BP1
Number of individuals with the variant: 1
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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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Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach. | Caputo SM | American journal of human genetics | 2021 | PMID: 34597585 |
High-throughput functional evaluation of BRCA2 variants of unknown significance. | Ikegami M | Nature communications | 2020 | PMID: 32444794 |
Minigene Splicing Assays Identify 12 Spliceogenic Variants of BRCA2 Exons 14 and 15. | Fraile-Bethencourt E | Frontiers in genetics | 2019 | PMID: 31191615 |
Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. | Li JY | International journal of cancer | 2019 | PMID: 29752822 |
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. | Guidugli L | American journal of human genetics | 2018 | PMID: 29394989 |
Analysis of BRCA1/2 mutation spectrum and prevalence in unselected Chinese breast cancer patients by next-generation sequencing. | Li G | Journal of cancer research and clinical oncology | 2017 | PMID: 28664449 |
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 |
Deleterious BRCA1/2 mutations in an urban population of Black women. | Lynce F | Breast cancer research and treatment | 2015 | PMID: 26250392 |
Clear cell sarcoma of the kidney in a child with Fanconi anemia. | Trejo Bittar HE | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 2014 | PMID: 24735155 |
A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. | Jeyasekharan AD | Nature structural & molecular biology | 2013 | PMID: 24013206 |
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. | Guidugli L | Cancer research | 2013 | PMID: 23108138 |
BRCA1 and BRCA2 mutations in breast cancer patients from Venezuela. | Lara K | Biological research | 2012 | PMID: 23096355 |
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. | Karchin R | Cancer informatics | 2008 | PMID: 19043619 |
BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. | Claes K | British journal of cancer | 2004 | PMID: 15026808 |
BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. | Yang H | Science (New York, N.Y.) | 2002 | PMID: 12228710 |
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Text-mined citations for rs80359035 ...
HelpRecord last updated Oct 08, 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.