ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7505G>A (p.Arg2502His)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7505G>A (p.Arg2502His)
Variation ID: 52345 Accession: VCV000052345.58
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32356497 (GRCh38) [ NCBI UCSC ] 13: 32930634 (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 Oct 8, 2024 Jun 18, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7505G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg2502His missense NC_000013.11:g.32356497G>A NC_000013.10:g.32930634G>A NG_012772.3:g.46018G>A LRG_293:g.46018G>A LRG_293t1:c.7505G>A LRG_293p1:p.Arg2502His U43746.1:n.7733G>A - Protein change
- R2502H
- Other names
- p.R2502H:CGC>CAC
- NP_000050.3:p.Arg2502His
- 7733G>A
- Canonical SPDI
- NC_000013.11:32356496: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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 |
18955 | 19114 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2022 | RCV000045234.20 | |
Benign (4) |
reviewed by expert panel
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Jun 18, 2019 | RCV000083136.15 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2021 | RCV000131692.16 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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May 1, 2024 | RCV000588836.32 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV001081947.15 |
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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Benign
(Jun 18, 2019)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV001161616.2
First in ClinVar: Feb 16, 2020 Last updated: Jan 07, 2023 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00054 (less)
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Likely benign
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002064780.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Mar 09, 2021)
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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: SCV000210652.8
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 10486320, 24504028, 19043619, 24772314, 21702907, 25583476, 18824701, 10882858, 25415331, 22505045, 28222693, 27616075, 28263838, 30696104)
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Likely benign
(May 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: SCV005050910.4
First in ClinVar: Jun 17, 2024 Last updated: Oct 08, 2024 |
Comment:
BRCA2: BP4, BS3:Supporting, BS1
Number of individuals with the variant: 1
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Uncertain significance
(Feb 15, 2017)
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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: SCV000784917.2
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
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Likely benign
(Apr 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602788.2
First in ClinVar: Mar 08, 2017 Last updated: Feb 17, 2019 |
Comment:
The BRCA2 c.7505G>A; p.Arg2502His variant (rs56070345) is reported in patients with breast and ovarian cancer (Akbari 2011, Gayther 1999, Spearman 2008), but also in an … (more)
The BRCA2 c.7505G>A; p.Arg2502His variant (rs56070345) is reported in patients with breast and ovarian cancer (Akbari 2011, Gayther 1999, Spearman 2008), but also in an unaffected individual (Balabanski 2014). This variant is reported in ClinVar (Variation ID: 52345) and found in the general population with an overall allele frequency of 0.007% (17/246182 alleles) in the Genome Aggregation Database. The arginine at codon 2502 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, this variant has been previously identified by our laboratory in a patient who also carries a pathogenic truncating BRCA1 variant. Based on available information, this variant is considered to be likely benign. REFERENCES Akbari MR et al. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. J Med Genet. 2011 Nov;48(11):783-6. Balabanski L et al. Next-generation sequencing of BRCA1 and BRCA2 in breast cancer patients and control subjects. Mol Clin Oncol. 2014 May;2(3):435-439. Gayther SA et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet. 1999 Oct;65(4):1021-9. Spearman AD et al. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol. 2008 Nov 20;26(33):5393-400. (less)
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Benign
(Nov 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002025820.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
Testing laboratory: National Health Laboratory Service (NHLS)
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Likely benign
(Jun 28, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002531862.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010330.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Benign
(Dec 22, 2017)
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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: SCV000186728.7
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Oct 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000805764.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
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Benign
(Dec 29, 2015)
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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: SCV000902828.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
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Likely benign
(Aug 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133901.3
First in ClinVar: Jan 04, 2020 Last updated: Jan 03, 2022 |
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Benign
(Oct 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695072.3
First in ClinVar: Mar 17, 2018 Last updated: Nov 19, 2022 |
Comment:
Variant summary: BRCA2 c.7505G>A (p.Arg2502His) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of … (more)
Variant summary: BRCA2 c.7505G>A (p.Arg2502His) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-05 in 252472 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7505G>A has been reported in the literature in individuals affected with breast- or ovarian cancer (e.g. Akbari_2011, Gayther_1999, Spearman_2008, Bolognesi_2014, Cunningham_2014, Davies_2018, Kraus_2016, Momozawa_2018), but also in controls (Bolognesi_2014, Balabanski_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been observed at our laboratory and in prominent databases (UMD-BRCA1 c.5096G>A, p.Arg1699Gln; Our laboratory-BRCA1 c.68_69delAG; ARUP laboratories-BRCA1, pathogenic variant is not specified), providing supporting evidence for a benign role. Two publications reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect on splicing (Houdayer_2012), and no effect on the BRCA2/DSS1 interaction (Caleca_2019). Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with a predominant consensus as benign/likely benign (n=11) (VUS, n=2). Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Jan 27, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000073247.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
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Benign
(May 01, 2012)
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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: SCV000115210.3
First in ClinVar: Feb 06, 2014 Last updated: Sep 27, 2014 |
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Uncertain significance
(Feb 20, 2004)
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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,
unknown
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147109.2
First in ClinVar: Apr 01, 2014 Last updated: May 27, 2015 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Germany
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
Observation 4:
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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Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.834265 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Prevalence and Spectrum of BRCA Germline Variants in Central Italian High Risk or Familial Breast/Ovarian Cancer Patients: A Monocentric Study. | Foglietta J | Genes | 2020 | PMID: 32806537 |
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the BRCA1 and BRCA2 Genes. | Caleca L | Cancers | 2019 | PMID: 30696104 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
BRCA1 founder mutations and beyond in the Polish population: A single-institution BRCA1/2 next-generation sequencing study. | Kowalik A | PloS one | 2018 | PMID: 30040829 |
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. | Davies H | Nature medicine | 2017 | PMID: 28288110 |
Evaluation of the Ion Torrent PGM sequencing workflow for the routine rapid detection of BRCA1 and BRCA2 germline mutations. | Zanella I | Experimental and molecular pathology | 2017 | PMID: 28263838 |
Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study. | Lai KN | BMC cancer | 2017 | PMID: 28222693 |
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. | Kraus C | International journal of cancer | 2017 | PMID: 27616075 |
Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy. | Chen K | Proceedings of the National Academy of Sciences of the United States of America | 2015 | PMID: 25583476 |
Clinical application of micronucleus test: a case-control study on the prediction of breast cancer risk/susceptibility. | Bolognesi C | PloS one | 2014 | PMID: 25415331 |
Next-generation sequencing of BRCA1 and BRCA2 in breast cancer patients and control subjects. | Balabanski L | Molecular and clinical oncology | 2014 | PMID: 24772314 |
Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. | Cunningham JM | Scientific reports | 2014 | PMID: 24504028 |
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. | Houdayer C | Human mutation | 2012 | PMID: 22505045 |
Mutation screening of RAD51C in high-risk breast and ovarian cancer families. | Lu W | Familial cancer | 2012 | PMID: 22476429 |
Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. | Akbari MR | Journal of medical genetics | 2011 | PMID: 21965345 |
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. | Karchin R | Cancer informatics | 2008 | PMID: 19043619 |
Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. | Spearman AD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18824701 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Incidence of BRCA1/2 germ line alterations in a high risk cohort participating in a phase II chemoprevention trial. | Klemp J | European journal of cancer (Oxford, England : 1990) | 2000 | PMID: 10882858 |
The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. | Gayther SA | American journal of human genetics | 1999 | PMID: 10486320 |
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Text-mined citations for rs56070345 ...
HelpRecord last updated Oct 13, 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.