ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.518G>T (p.Gly173Val)
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.518G>T (p.Gly173Val)
Variation ID: 51810 Accession: VCV000051810.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32326500 (GRCh38) [ NCBI UCSC ] 13: 32900637 (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 Apr 1, 2014 Feb 14, 2024 Dec 17, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.518G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Gly173Val missense NC_000013.11:g.32326500G>T NC_000013.10:g.32900637G>T NG_012772.3:g.16021G>T LRG_293:g.16021G>T LRG_293t1:c.518G>T LRG_293p1:p.Gly173Val U43746.1:n.746G>T - Protein change
- G173V
- Other names
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- Canonical SPDI
- NC_000013.11:32326499:G:T
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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 0.00001
Exome Aggregation Consortium (ExAC) 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 |
18445 | 18602 |
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 (1) |
criteria provided, single submitter
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Dec 17, 2022 | RCV000044598.6 | |
Uncertain significance (1) |
no assertion criteria provided
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May 29, 2002 | RCV000113738.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 24, 2021 | RCV000213680.4 |
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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Uncertain significance
(Jul 28, 2020)
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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: SCV001735484.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces glycine with valine at codon 173 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with valine at codon 173 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). Functional RNA studies using minigene splicing assays reported conflicted findings of a partial splicing defect and no detectable defect (PMID: 20215541, 23983145). This variant has been reported in an individual with suspected hereditary breast cancer (PMID: 28205045) and another individual affected with triple-negative breast cancer (PMID: 25682074). This variant has been identified in 3/251340 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
(Aug 24, 2021)
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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: SCV000273887.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.G173V variant (also known as c.518G>T), located in coding exon 6 of the BRCA2 gene, results from a G to T substitution at nucleotide … (more)
The p.G173V variant (also known as c.518G>T), located in coding exon 6 of the BRCA2 gene, results from a G to T substitution at nucleotide position 518. The glycine at codon 173 is replaced by valine, an amino acid with dissimilar properties. This alteration was identified in a cohort of high-risk breast and ovarian cancer patients (Park B et al. Breast Cancer Res. Treat., 2017 May;163:139-150). A functional assay shows that this alteration behaved like wildtype in a spontaneous homologous repair assay, however, the assay was not robust enough to predict clinical relevance of tested variants (Balia C et al. Breast Cancer Res. Treat., 2011 Oct;129:1001-9). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, the literature harbors conflicting results in terms of the generation of abnormal transcripts from a splicing minigene assay with one paper reporting exon 7 skipping as a minor isoform while another reports no abnormal transcripts (Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67; Di Giacomo D et al. Hum. Mutat., 2013 Nov;34:1547-57). This amino acid position is well not conserved on limited sequence alignment. 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)
Number of individuals with the variant: 1
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Uncertain significance
(Dec 17, 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: SCV000072611.7
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the BRCA2 protein (p.Gly173Val). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the BRCA2 protein (p.Gly173Val). 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. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 21671020). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 51810). This missense change has been observed in individual(s) with breast cancer (PMID: 25682074, 28205045). This variant is present in population databases (rs28897702, gnomAD 0.003%). (less)
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Uncertain significance
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147058.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Asian
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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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Characteristics of BRCA1/2 mutations carriers including large genomic rearrangements in high risk breast cancer patients. | Park B | Breast cancer research and treatment | 2017 | PMID: 28205045 |
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. | Wong-Brown MW | Breast cancer research and treatment | 2015 | PMID: 25682074 |
Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements. | Di Giacomo D | Human mutation | 2013 | PMID: 23983145 |
Multiple sequence variants of BRCA2 exon 7 alter splicing regulation. | Gaildrat P | Journal of medical genetics | 2012 | PMID: 22962691 |
Effect of the overexpression of BRCA2 unclassified missense variants on spontaneous homologous recombination in human cells. | Balia C | Breast cancer research and treatment | 2011 | PMID: 21671020 |
A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. | Sanz DJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2010 | PMID: 20215541 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs28897702 ...
HelpRecord last updated Mar 30, 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.