ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.3749A>G (p.Glu1250Gly)
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(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.3749A>G (p.Glu1250Gly)
Variation ID: 51515 Accession: VCV000051515.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32338104 (GRCh38) [ NCBI UCSC ] 13: 32912241 (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 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.3749A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Glu1250Gly missense NC_000013.11:g.32338104A>G NC_000013.10:g.32912241A>G NG_012772.3:g.27625A>G LRG_293:g.27625A>G LRG_293t1:c.3749A>G LRG_293p1:p.Glu1250Gly U43746.1:n.3977A>G - Protein change
- E1250G
- Other names
- p.E1250G:GAA>GGA
- Canonical SPDI
- NC_000013.11:32338103:A:G
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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
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 |
18726 | 18884 |
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
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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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Likely benign (1) |
criteria provided, single submitter
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Dec 31, 2023 | RCV000044256.13 | |
Likely benign (3) |
criteria provided, single submitter
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Oct 23, 2023 | RCV000113214.5 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Sep 16, 2023 | RCV000129769.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2021 | RCV000212231.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV001194411.5 |
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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Likely benign
(May 02, 2016)
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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: SCV000903264.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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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: SCV003846839.1
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
(Aug 28, 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: SCV001363946.4
First in ClinVar: Jun 22, 2020 Last updated: Oct 04, 2023 |
Comment:
Variant summary: BRCA2 c.3749A>G (p.Glu1250Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.3749A>G (p.Glu1250Gly) results in a non-conservative amino acid change in 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 4e-06 in 246920 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3749A>G has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (e.g. Caux-Moncoutier_2011, Lu_2012, Zuntini_2018, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 21120943, 22476429, 30254663, 33471991). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, and three as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 16, 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: SCV000184578.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.E1250G variant (also known as c.3749A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide … (more)
The p.E1250G variant (also known as c.3749A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3749. The glutamic acid at codon 1250 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier V et al. Hum Mutat, 2011 Mar;32:325-34; Lu W et al. Fam Cancer, 2012 Sep;11:381-5; Zuntini R et al. Front Genet, 2018 Sep;9:378). In one study, this variant was reported in 2/60,466 breast cancer cases as well as in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not 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
(Dec 06, 2019)
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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: SCV000887796.3
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2021 |
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Uncertain significance
(Nov 05, 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: SCV000210323.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); Observed in individuals with a personal and/or family history of breast and/or … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011, Lu 2012, Zutini 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3977A>G; This variant is associated with the following publications: (PMID: 21120943, 22476429, 25556971, 30254663) (less)
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Likely benign
(Dec 31, 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: SCV000072269.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
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Likely Benign
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004845216.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Number of individuals with the variant: 3
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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: SCV000146291.1
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
Ethnicity/Population group: Western European
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Likely benign
(Sep 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228396.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
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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 |
Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help? | Zuntini R | Frontiers in genetics | 2018 | PMID: 30254663 |
Mutation screening of RAD51C in high-risk breast and ovarian cancer families. | Lu W | Familial cancer | 2012 | PMID: 22476429 |
EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. | Caux-Moncoutier V | Human mutation | 2011 | PMID: 21120943 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs56400215 ...
HelpRecord last updated May 08, 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.