ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.4189G>A (p.Glu1397Lys)
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(7); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.4189G>A (p.Glu1397Lys)
Variation ID: 37887 Accession: VCV000037887.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32338544 (GRCh38) [ NCBI UCSC ] 13: 32912681 (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 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.4189G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Glu1397Lys missense NC_000013.11:g.32338544G>A NC_000013.10:g.32912681G>A NG_012772.3:g.28065G>A LRG_293:g.28065G>A LRG_293t1:c.4189G>A LRG_293p1:p.Glu1397Lys U43746.1:n.4417G>A - Protein change
- E1397K
- Other names
- p.E1397K:GAA>AAA
- 4417G>A
- Canonical SPDI
- NC_000013.11:32338543: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
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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 |
18734 | 18892 |
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 (2) |
no assertion criteria provided
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Nov 23, 2009 | RCV000031468.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 24, 2023 | RCV000044370.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV000203656.11 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 8, 2023 | RCV000509937.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 13, 2023 | RCV000586214.8 | |
not provided (1) |
no classification provided
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- | RCV003483437.1 |
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
(Jul 24, 2023)
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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: SCV000694750.3
First in ClinVar: Mar 17, 2018 Last updated: Aug 26, 2023 |
Comment:
Variant summary: BRCA2 c.4189G>A (p.Glu1397Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.4189G>A (p.Glu1397Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 241566 control chromosomes in gnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4189G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (example: Morgan_2010, Hondow_2011, Mattocks_2010, Kaur_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant has been observed to co-occur with a pathogenic BRCA2 c.4163_4164delCTinsA in at least 6 individuals (3 internal specimens, 3 BIC individuals) providing supporting evidence for a benign role. The variant has also been reported to co-occur with another pathogenic BRCA2 variant, c.4169delT (Mattocks_2010; phase not specified). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21702907, 18724707, 20167696, 20127978, 29700634). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS: n=6; LB: n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Jan 10, 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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Invitae
Accession: SCV000072383.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1397 of the BRCA2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1397 of the BRCA2 protein (p.Glu1397Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or at risk for hereditary breast and ovarian cancer (PMID: 20127978, 29700634). ClinVar contains an entry for this variant (Variation ID: 37887). 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 with a negative predictive value of 95%. 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
(Nov 03, 2017)
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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: SCV000889046.3
First in ClinVar: Mar 17, 2018 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jun 13, 2023)
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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: SCV000210330.15
First in ClinVar: Feb 24, 2015 Last updated: Jun 24, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 4417G>A; This variant is associated with the following publications: (PMID: 18724707, 20167696, 21702907, 20127978, 27376475, 10923033, 29700634, 33471991, 29884841, 32377563) (less)
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Uncertain significance
(Aug 23, 2022)
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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: SCV000688858.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 1397 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with lysine at codon 1397 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer and in some of these individuals this variant was observed in cis with BRCA2 c.4163_4164delCTinsA (PMID: 20127978, 27376475, 33471991;Leiden Open Variation Database DB-ID BRCA2_003742, kConFab database, Color internal data). 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
(Jun 23, 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: SCV002533857.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.4189G>A (p.E1397K) variant has been reported in heterozygosity in individuals with or at risk of developing hereditary breast and/or ovarian cancer (PMID: 33471991, … (more)
The BRCA2 c.4189G>A (p.E1397K) variant has been reported in heterozygosity in individuals with or at risk of developing hereditary breast and/or ovarian cancer (PMID: 33471991, 29700634, 27376475, 20127978). It was not observed in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 37887). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Likely benign
(Mar 23, 2023)
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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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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003848751.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA2 exon 11 coldspot. Reclassification based on statistical prior probability.
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Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
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Uncertain significance
(Dec 08, 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: SCV000607796.5
First in ClinVar: Oct 23, 2017 Last updated: May 01, 2024 |
Comment:
The p.E1397K variant (also known as c.4189G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide … (more)
The p.E1397K variant (also known as c.4189G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4189. The glutamic acid at codon 1397 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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)
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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
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146390.1
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: 2
Ethnicity/Population group: Western European
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Uncertain significance
(Nov 23, 2009)
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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: SCV000054073.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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BRCA2-related disorder
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228964.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 08-15-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 08-15-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Family history of cancer (present)
Indication for testing: Family Testing
Age: 40-49 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-08-15
Testing laboratory interpretation: Uncertain significance
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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 |
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients. | Kaur RP | Medical oncology (Northwood, London, England) | 2018 | PMID: 29700634 |
Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. | Schenkel LC | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27376475 |
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
Interlaboratory diagnostic validation of conformation-sensitive capillary electrophoresis for mutation scanning. | Mattocks CJ | Clinical chemistry | 2010 | PMID: 20167696 |
Genetic diagnosis of familial breast cancer using clonal sequencing. | Morgan JE | Human mutation | 2010 | PMID: 20127978 |
Computational and structural investigation of deleterious functional SNPs in breast cancer BRCA2 gene. | Rajasekaran R | Sheng wu gong cheng xue bao = Chinese journal of biotechnology | 2008 | PMID: 18724707 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs28897726 ...
HelpRecord last updated Jun 02, 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.