ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.20G>A (p.Arg7His)
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(5); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.20G>A (p.Arg7His)
Variation ID: 184875 Accession: VCV000184875.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43124077 (GRCh38) [ NCBI UCSC ] 17: 41276094 (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 Dec 26, 2017 May 1, 2024 Jan 31, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- R7H
- Other names
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- Canonical SPDI
- NC_000017.11:43124076:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functionally_normal Sequence Ontology [SO:0002219]
- The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.20G>A, a MISSENSE variant, produced a function score of -0.54, corresponding to a functional classification of FUNCTIONAL. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute, University of Washington]
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
12940 | 14730 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 20, 2023 | RCV000164210.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764129.3 | |
Likely benign (3) |
no assertion criteria provided
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Feb 2, 2024 | RCV001072325.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000543291.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 13, 2022 | RCV000588310.6 |
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
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
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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
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Breast-ovarian cancer, familial, susceptibility to, 1 Pancreatic cancer, susceptibility to, 4 Fanconi anemia, complementation group S
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895102.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Feb 26, 2022)
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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: SCV002538091.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA1 c.20G>A (p.R7H) variant has been reported in heterozygosity in at least one individual with a personal and/or family history of hereditary breast and/or … (more)
The BRCA1 c.20G>A (p.R7H) variant has been reported in heterozygosity in at least one individual with a personal and/or family history of hereditary breast and/or ovarian cancer (PMID: 16267036). In silico predictions of the variant's effect on protein function are inconclusive. However, homology-directed DNA repair, BARD1 binding, E3 ubiquitin ligase, and haploid cell proliferation assays demonstrated the normal function of the protein in the presence of the variant (PMID: 30209399, 25823446). This variant was observed in 6/34592 chromosomes in the Latino population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 184875). 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
(Jul 13, 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: SCV002047271.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
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Likely benign
(May 08, 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: SCV000214831.6
First in ClinVar: Mar 24, 2015 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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Uncertain significance
(Aug 03, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698916.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The BRCA1 c.20G>A (p.Arg7His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant … (more)
Variant summary: The BRCA1 c.20G>A (p.Arg7His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120706 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in at least one patient with HBOC without strong support for pathogenicity (Judkins_2005). A functional study (Starita_2015) reported the variant to be as proficient in homology-directed DNA repair as is the wild type BRCA1 indicating the variant to be in the neutral spectrum. In addition, multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Considering all evidence, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Jan 29, 2018)
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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: SCV000329116.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 17, 2018 |
Comment:
This variant is denoted BRCA1 c.20G>A at the cDNA level, p.Arg7His (R7H) at the protein level, and results in the change of an Arginine to … (more)
This variant is denoted BRCA1 c.20G>A at the cDNA level, p.Arg7His (R7H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). Using alternate nomenclature, this variant would be defined as BRCA1 139G>A. This variant has been observed in at least one individual referred for BRCA1 testing (Judkins 2005). It was demonstrated to have E3 ligase activity and BARD1 interaction similar to wildtype and was able to rescue homology-directed repair in a cell line lacking endogenous BRCA1 (Starita 2015). BRCA1 Arg7His was not observed in large population cohorts (Lek 2016). This variant is located in the RING domain and a region known to interact with BRD7 (Harte 2010, Borg 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Arg7His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Likely benign
(Apr 20, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000903775.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jan 31, 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: SCV000635828.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 7 of the BRCA1 protein (p.Arg7His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 7 of the BRCA1 protein (p.Arg7His). This variant is present in population databases (rs144792613, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 184875). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 25823446, 30209399). 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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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, 1
Affected status: yes
Allele origin:
germline
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Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228312.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
BS1(Supporting)+BS3(Strong)+BP4(Supporting) 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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Likely benign
(Feb 02, 2024)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV004244210.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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not provided
(-)
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no classification provided
Method: in vitro
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Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
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Brotman Baty Institute, University of Washington
Accession: SCV001237685.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
FUNCTIONAL:-0.539420688452674
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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
Help
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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functionally_normal
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Method citation(s):
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Brotman Baty Institute, University of Washington
Accession: SCV001237685.1
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Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.20G>A, a MISSENSE variant, produced a function score of -0.54, corresponding to a functional classification of FUNCTIONAL. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.20G>A, a MISSENSE variant, produced a function score of -0.54, corresponding to a functional classification of FUNCTIONAL. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. (less)
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. | Starita LM | Genetics | 2015 | PMID: 25823446 |
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
Text-mined citations for rs144792613 ...
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.