ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4675+3A>G
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.4675+3A>G
Variation ID: 185264 Accession: VCV000185264.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 43074328 (GRCh38) [ NCBI UCSC ] 17: 41226345 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 24, 2015 May 1, 2024 Apr 21, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- -
- Canonical SPDI
- NC_000017.11:43074327:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
12894 | 14680 |
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. |
---|---|---|---|---|
Uncertain significance (1) |
criteria provided, single submitter
|
Jul 22, 2018 | RCV000164653.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 21, 2023 | RCV000463988.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Sep 12, 2017 | RCV000503121.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 20, 2023 | RCV000985423.6 | |
Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001353748.2 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Jul 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133594.3
First in ClinVar: Jan 05, 2020 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Mar 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004234650.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Apr 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000549316.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 185264). This variant has been observed in individual(s) with BRCA1-related conditions (PMID: 32438681). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. (less)
|
|
Uncertain significance
(Sep 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918708.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The BRCA1 c.4675+3A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more)
Variant summary: The BRCA1 c.4675+3A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121176 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS), until additional information becomes available. (less)
|
|
Uncertain significance
(Jul 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215318.6
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.4675+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 13 in the BRCA1 gene. This nucleotide position is … (more)
The c.4675+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 13 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591533.2 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 c.4675+3A>G variant was not identified in the literature nor was it identified in the LOVD 3.0 and UMD-LSDB database. The variant was identified … (more)
The BRCA1 c.4675+3A>G variant was not identified in the literature nor was it identified in the LOVD 3.0 and UMD-LSDB database. The variant was identified in dbSNP (rs80358082) as “with pathogenic, uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, and Integrated Genetics). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In other laboratories, a likely pathogenic variant was observed at the same loci with a different nucleotide change (c.4675+3A>T). The c.4675+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 2 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicted a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
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 |
---|---|---|---|---|
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 |
Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11. | Baert A | Human mutation | 2018 | PMID: 29280214 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs80358082 ...
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.