ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7857G>C (p.Trp2619Cys)
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(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7857G>C (p.Trp2619Cys)
Variation ID: 438744 Accession: VCV000438744.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32362574 (GRCh38) [ NCBI UCSC ] 13: 32936711 (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 Jan 1, 2018 May 1, 2024 Apr 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7857G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Trp2619Cys missense NC_000013.11:g.32362574G>C NC_000013.10:g.32936711G>C NG_012772.3:g.52095G>C LRG_293:g.52095G>C LRG_293t1:c.7857G>C LRG_293p1:p.Trp2619Cys - Protein change
- W2619C
- Other names
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- Canonical SPDI
- NC_000013.11:32362573:G:C
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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 |
18723 | 18699 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 12, 2023 | RCV000574330.10 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Sep 19, 2017 | RCV000664330.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 8, 2022 | RCV000692296.4 |
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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Likely pathogenic
(Sep 19, 2017)
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criteria provided, single submitter
Method: research
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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School of Basic Medicine, Fourth Military Medical University
Additional submitter:
General Surgery, Xijing Hospital
Accession: SCV000599883.1
First in ClinVar: Jul 29, 2018 Last updated: Jul 29, 2018 |
Comment:
This variation is identified in a proband with familial breast cancer and verified by co-segregation analysis in her family.
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast Cancer
Age: 30-39 years
Sex: female
Ethnicity/Population group: Chinese
Geographic origin: China
Method: The amplified DNA was captured with a hereditary tumor related Gene Panel using biotinylated oligo-probes (MyGenostics GenCap Enrichment technologies). The probes were designed to tile along 110 hereditary tumor related genes. The capture experiment was conducted according to manufacturer’s protocol. After HiSeq 2000 sequencing, high-quality reads were retrieved from raw reads by filtering out the low quality reads and adaptor sequences using the Solexa QA package and the cutadapt program (http://code.google.com/p/cutadapt/), respectively. SOAPaligner program was then used to align the clean read sequences to the human reference genome (hg19). After the PCR duplicates were removed by the Picard software, the SNPs was firstly identified using the SOAPsnp program (http://soap.genomics.org.cn/soapsnp.html). Subsequently, we realigned the reads to the reference genome using BWA and identified the insertions or deletions (InDels) using the GATK program (http://www.broadinstitute.org/gsa/wiki/index.php/Home_Page). The identified SNPs and InDels were annotated using the Exome-assistant program (http://122.228.158.106/exomeassistant). MagicViewer was used to view the short read alignment and validate the candidate SNPs and InDels. Nonsynonymous variants were evaluated by four algorithms, Ployphen, SIFT, PANTHER and Pmut, as described previously to determine pathogenicity.
Testing laboratory: MyGenostics
Date variant was reported to submitter: 2017-04-21
Testing laboratory interpretation: Uncertain significance
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Pathogenic
(Apr 12, 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: SCV000661222.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.W2619C pathogenic mutation (also known as c.7857G>C), located in coding exon 16 of the BRCA2 gene, results from a G to C substitution at … (more)
The p.W2619C pathogenic mutation (also known as c.7857G>C), located in coding exon 16 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7857. The tryptophan at codon 2619 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in several Chinese breast and/or ovarian cancer cohorts (Yang H et al. Science, 2002 Sep;297:1837-48; Liang Y et al. Med. Sci. Monit., 2018 Apr;24:2465-2475; Li JY et al. Int. J. Cancer, 2019 01;144:281-289; Bhaskaran SP et al. Int. J. Cancer, 2019 08;145:962-973; Gao X et al. Hum. Mutat., 2019 Dec). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). Two other alterations at the same codon, p.W2619G (c.7855T>G) and p.W2619R (c.7855T>C), have also been found to be non-functional in a homology-directed DNA repair (HDR) assay and have been reported as either likely pathogenic or pathogenic by our laboratory (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Uncertain significance
(Apr 15, 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: SCV000904373.2
First in ClinVar: May 20, 2019 Last updated: Jun 22, 2020 |
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Uncertain significance
(Apr 08, 2022)
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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: SCV000820110.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of … (more)
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 29681614, 29752822, 30702160). ClinVar contains an entry for this variant (Variation ID: 438744). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 33609447). 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. This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 2619 of the BRCA2 protein (p.Trp2619Cys). (less)
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Uncertain significance
(Mar 02, 2020)
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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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BRCAlab, Lund University
Accession: SCV004243785.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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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 |
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients. | Gao X | Human mutation | 2020 | PMID: 31825140 |
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients. | Bhaskaran SP | International journal of cancer | 2019 | PMID: 30702160 |
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 |
Prevalence and Spectrum of BRCA1/2 Germline Mutations in Women with Breast Cancer in China Based on Next-Generation Sequencing. | Liang Y | Medical science monitor : international medical journal of experimental and clinical research | 2018 | PMID: 29681614 |
BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. | Yang H | Science (New York, N.Y.) | 2002 | PMID: 12228710 |
Text-mined citations for rs80359011 ...
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.