ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.6952C>G (p.Arg2318Gly)
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.6952C>G (p.Arg2318Gly)
Variation ID: 409599 Accession: VCV000409599.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32346841 (GRCh38) [ NCBI UCSC ] 13: 32920978 (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 29, 2017 May 1, 2024 Sep 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.6952C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg2318Gly missense NC_000013.11:g.32346841C>G NC_000013.10:g.32920978C>G NG_012772.3:g.36362C>G LRG_293:g.36362C>G LRG_293t1:c.6952C>G LRG_293p1:p.Arg2318Gly - Protein change
- R2318G
- Other names
- p.Arg2318Gly
- Canonical SPDI
- NC_000013.11:32346840:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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 | 18881 |
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
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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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Oct 20, 2022 | RCV000461532.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 18, 2016 | RCV000485650.1 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 4, 2023 | RCV000573163.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 21, 2022 | RCV001839454.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 21, 2022 | RCV002275033.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 12, 2021 | RCV003150219.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 17, 2023 | RCV003476090.1 |
Submissions - Germline
Classification
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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
(Nov 18, 2016)
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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: SCV000572316.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted BRCA2 c.6952C>G at the cDNA level, p.Arg2318Gly (R2318G) at the protein level, and results in the change of an Arginine to … (more)
This variant is denoted BRCA2 c.6952C>G at the cDNA level, p.Arg2318Gly (R2318G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 7180C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg2318Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2318Gly occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Arg2318Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Feb 19, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000910262.3
First in ClinVar: May 20, 2019 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces arginine with glycine at codon 2318 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glycine at codon 2318 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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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Uncertain significance
(Feb 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal carcinoma
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002098401.1
First in ClinVar: Mar 03, 2022 Last updated: Mar 03, 2022 |
Comment:
A heterozygous missense variation in exon 13 of the BRCA2 gene that results in the amino acid substitution of Glycine for Arginine at codon 2318 … (more)
A heterozygous missense variation in exon 13 of the BRCA2 gene that results in the amino acid substitution of Glycine for Arginine at codon 2318 was detected. The observed variant c.6952C>G (p.Arg2318Gly) is documented as a variant of uncertain significance in hereditary cancer-predisposing syndrome in the ClinVar database (VCV000409599.10). The variant has not been reported in the 1000 genomes and gnomAD database respectively. The in silico predictions of the variant are probably damaging by PolyPhen-2 and damaging by SIFT, MutationTaster2, and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. (less)
Clinical Features:
Carcinoma of esophagus (present)
Age: 60-69 years
Sex: male
Ethnicity/Population group: Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean > 80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Uncertain significance
(Feb 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Malignant tumor of esophagus
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002562748.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
Comment:
A heterozygous missense variation in exon 13 of the BRCA2 gene that results in the amino acid substitution of Glycine for Arginine at codon 2318 … (more)
A heterozygous missense variation in exon 13 of the BRCA2 gene that results in the amino acid substitution of Glycine for Arginine at codon 2318 was detected. The observed variant c.6952C>G (p.Arg2318Gly) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across primates. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. (less)
Age: 60-69 years
Sex: male
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Uncertain significance
(Oct 20, 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: SCV000549866.9
First in ClinVar: Apr 17, 2017 Last updated: Nov 11, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2318 of the BRCA2 protein (p.Arg2318Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2318 of the BRCA2 protein (p.Arg2318Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 409599). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. 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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Uncertain significance
(Jul 12, 2021)
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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
Accession: SCV003838830.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Uncertain significance
(Sep 17, 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: SCV004211947.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Feb 04, 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: SCV000666090.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.R2318G variant (also known as c.6952C>G), located in coding exon 12 of the BRCA2 gene, results from a C to G substitution at nucleotide … (more)
The p.R2318G variant (also known as c.6952C>G), located in coding exon 12 of the BRCA2 gene, results from a C to G substitution at nucleotide position 6952. The arginine at codon 2318 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002098401.1
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002562748.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Text-mined citations for rs80358920 ...
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.