ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7463G>A (p.Arg2488Lys)
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.
Uncertain significance(4); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7463G>A (p.Arg2488Lys)
Variation ID: 52336 Accession: VCV000052336.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32356455 (GRCh38) [ NCBI UCSC ] 13: 32930592 (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 May 1, 2024 Nov 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7463G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg2488Lys missense NC_000013.11:g.32356455G>A NC_000013.10:g.32930592G>A NG_012772.3:g.45976G>A LRG_293:g.45976G>A LRG_293t1:c.7463G>A LRG_293p1:p.Arg2488Lys U43746.1:n.7691G>A - Protein change
- R2488K
- Other names
- p.R2488K:AGA>AAA
- 7691G>A
- Canonical SPDI
- NC_000013.11:32356454: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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
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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
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 |
18776 | 18934 |
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
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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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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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May 28, 2019 | RCV000077401.22 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 19, 2020 | RCV000168600.15 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jul 23, 2018 | RCV000563199.15 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jun 8, 2022 | RCV001284108.17 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 16, 2023 | RCV001410830.14 |
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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Uncertain significance
(Aug 07, 2015)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000575726.1
First in ClinVar: May 07, 2017 Last updated: May 07, 2017 |
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Likely benign
(Oct 19, 2020)
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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: SCV000695069.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 11, 2020 |
Comment:
Variant summary: BRCA2 c.7463G>A (p.Arg2488Lys) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of … (more)
Variant summary: BRCA2 c.7463G>A (p.Arg2488Lys) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7463G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer and acute lymphoblastic leukemia (Claes_2004, Caux-Moncoutier_2009, de Smith_2019). Claes_2004 indicated the variant did not segregate with disease for one of the affected families. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, co-occurrences with other pathogenic variants have been reported (BRCA2 c.2745_2746delTT , p.Val917LysfsX18; BRCA1 c.1961dup, p.Tyr655ValfsX18; BRCA1 c.4183C>T, p.Gln1395X; BRCA1 c.IVS21+1G>T , c.5332+1G>T; BRCA1 c.4389C>A , p.Tyr1463X ; BRCA1 442_4357del , p.Glu149TyrfsX2, in UMD database), providing supporting evidence for a benign role. Although the variant is not located in a commonly known location to affect splicing (ie, within +/- 2 bp of an exon/intron junction), two publications found the variant to not affect splicing via functional studies (Caux-Moncoutier_2009, Houdayer_2012). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Mar 31, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000689049.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744518.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Uncertain significance
(Jan 22, 2016)
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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: SCV000488203.2
First in ClinVar: May 27, 2015 Last updated: Dec 24, 2022 |
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Uncertain significance
(Jun 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469714.2
First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022 |
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Likely benign
(May 26, 2020)
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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: SCV000210650.12
First in ClinVar: Mar 29, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 25348012, 24817641, 19043619, 19471317, 20858050, 21673748, 22505045, 15026808, 27974384, 31102422, 31131967)
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Likely benign
(Nov 16, 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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Invitae
Accession: SCV001612882.4
First in ClinVar: May 16, 2021 Last updated: Feb 20, 2024 |
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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001139180.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Jul 23, 2018)
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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: SCV000661177.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550347.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
BRCA2, EXON15, c.7463G>A, p.Arg2488Lys, Heterozygous, Likely BenignrnThe BRCA2 p.Arg2488Lys variant was identified in 3 of 7698 proband chromosomes (frequency: 0.0004) from individuals or families with … (more)
BRCA2, EXON15, c.7463G>A, p.Arg2488Lys, Heterozygous, Likely BenignrnThe BRCA2 p.Arg2488Lys variant was identified in 3 of 7698 proband chromosomes (frequency: 0.0004) from individuals or families with breast or ovarian cancer (Claes 2004, Caux-Moncoutier 2009). The variant was also identified in dbSNP (ID: rs80358968) as "With other allele", ClinVar (classified as likely benign by GeneDx, Ambry Genetics, SCRP, Color and Integrated Genetics/Laboratory Corporation of America; and as uncertain significance by four submitters), LOVD 3.0 (14x), and UMD-LSDB (1x as neutral). In the UMD-LSDB database, the variant was identified in multiple cases as co-occurring with pathogenic BRCA1 variants (c.1961dup, p.Tyr655ValfsX18; c.4183C>T, p.Gln1395X; c.IVS21+1G>T, r.spl?; c.4389C>A, p.Tyr1463X; and c.442_4357del, p.Glu149TyrfsX2) and a pathogenic BRCA2 variant (c.2745_2746delTT, p.Val917LysfsX18), increasing the likelihood that the p.Arg2488Lys variant does not have clinical significance. The variant was identified in control databases in 3 of 246180 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33578 chromosomes (freq: 0.00003), European in 2 of 111652 chromosomes (freq: 0.00002), but not in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg2488 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The literature suggests a neutral classification of the variant. Caux-Moncoutier (2009) used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. In addition, Claes (2004) found that the variant did not segregate with disease in one family. In addition, several in silico and in vitro studies using PAXgene, Minigene systems or functional evidence identified no change and classified the variant neutral with no effect on splicing (Houdayer 2012, Martelotto 2014). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.rnAssessment Date: 2019/07/22rnReferences (PMIDs): 15026808, 19471317, 22505045, 25348012, 19043619 (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906359.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
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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: SCV000147095.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Western European, Latin American, Caribbean
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Likely benign
(Nov 29, 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: SCV000109198.3
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954475.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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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 |
A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays. | Biswas K | NPJ genomic medicine | 2020 | PMID: 33293522 |
Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children. | de Smith AJ | Genes, chromosomes & cancer | 2019 | PMID: 31102422 |
BRCA Testing by Single-Molecule Molecular Inversion Probes. | Neveling K | Clinical chemistry | 2017 | PMID: 27974384 |
Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex. | Doss CG | Cell biochemistry and biophysics | 2014 | PMID: 24817641 |
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 |
Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. | Théry JC | European journal of human genetics : EJHG | 2011 | PMID: 21673748 |
A one-step prescreening for point mutations and large rearrangement in BRCA1 and BRCA2 genes using quantitative polymerase chain reaction and high-resolution melting curve analysis. | Coulet F | Genetic testing and molecular biomarkers | 2010 | PMID: 20858050 |
Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study. | Caux-Moncoutier V | European journal of human genetics : EJHG | 2009 | PMID: 19471317 |
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 |
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Text-mined citations for rs80358968 ...
HelpRecord last updated Jul 15, 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.