ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.442-1G>T
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.
Likely pathogenic(2); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.442-1G>T
Variation ID: 462651 Accession: VCV000462651.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43099881 (GRCh38) [ NCBI UCSC ] 17: 41251898 (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 Jul 15, 2018 May 1, 2024 Jan 29, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:43099880:C: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
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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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
12881 | 14666 |
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
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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV000548280.10 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Apr 30, 2023 | RCV000663008.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000781007.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 6, 2022 | RCV001022460.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 9, 2022 | RCV001837951.4 |
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
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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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Likely pathogenic
(Feb 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786017.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Likely pathogenic
(Oct 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial breast-ovarian cancer 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434978.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.442-1G>T variant in the BRCA1 gene disrupts the canonical splice acceptor site in intron 7 and is predicted to result in abnormal mRNA splicing. … (more)
This c.442-1G>T variant in the BRCA1 gene disrupts the canonical splice acceptor site in intron 7 and is predicted to result in abnormal mRNA splicing. This variant has an extremely low frequency in large databases of genetic variation in the general population. Loss of function variants in the BRCA1 gene have been associated with familial breast-ovarian cancer-1 (BROVCA1, MIM# 604370). Therefore, this c.442-1G>T variant in the BRCA1 gene is classified as likely pathogenic. (less)
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Uncertain significance
(Mar 06, 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: SCV002537751.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA1 c.442-1G>T variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30702160). It was observed in 2/35438 chromosomes in the Latino/Admixed … (more)
The BRCA1 c.442-1G>T variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30702160). It was observed in 2/35438 chromosomes in the Latino/Admixed American population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 462651). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). However, this canonical splice site variant is predicted to result in aberrant splicing, potentially leading to a known naturally occurring isoform, the in-frame deletion of a single amino acid, p.Gln148del (PMID: 24569164). The overall evidence is inconsistent with ACMG/AMP requirements for a classification of benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Feb 09, 2022)
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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: SCV002098205.2
First in ClinVar: Feb 26, 2022 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in aberrant splicing, potentially leading to a known naturally occurring isoform, the in-frame deletion of a single amino … (more)
Canonical splice site variant predicted to result in aberrant splicing, potentially leading to a known naturally occurring isoform, the in-frame deletion of a single amino acid, p.Gln148del (Colombo 2014); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 561-1G>T and IVS7-1G>T; This variant is associated with the following publications: (PMID: 27008870, 24569164, 30702160) (less)
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Uncertain significance
(Mar 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004037357.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
The c.442-1G>T variant in the BRCA1 gene is a heterozygous canonical splice site variant, which affects an acceptor splice site in intron 6 (23 introns … (more)
The c.442-1G>T variant in the BRCA1 gene is a heterozygous canonical splice site variant, which affects an acceptor splice site in intron 6 (23 introns total; NM_007300.4). A substitution at this site is predicted to disrupt mRNA splicing and likely results in an absent or disrupted protein product. Computational splicing tools have mixed results, where several predict the 3' acceptor site to be abolished, but also predict the strengthening of a cryptic 3' acceptor site that would only result in an in-frame deletion of several amino acids. There is some experimental data to show that the latter scenario may be true (PMID: 24569164). Currently, we do not definitively know which effect on the protein this variant will cause. This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (2/282,812), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this variant has not been reported in individuals affected with Hereditary Breast and Ovarian Cancer. Heterozygous loss-of-function variants in BRCA1, distal to this variant have been described to be associated with an increased risk of developing breast and ovarian cancer. However, the exact risk of breast and ovarian cancer, if any, conferred by this specific variant has not been determined. (less)
Clinical Features:
Unaffected (present)
Age: 30-39 years
Sex: female
Ethnicity/Population group: Hispanic Americans
Geographic origin: Ecuador
Tissue: buccal swab
Secondary finding: yes
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Uncertain significance
(Apr 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004215150.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jan 02, 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: SCV000635975.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 6 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 6 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (no rsID available, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30702160). ClinVar contains an entry for this variant (Variation ID: 462651). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 7 (also known as exon 8 in the literature) (PMID: 24569164). 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
(Jan 29, 2024)
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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: SCV000918755.2
First in ClinVar: Jun 02, 2019 Last updated: Mar 30, 2024 |
Comment:
Variant summary: BRCA1 c.442-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: BRCA1 c.442-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splicing acceptor site, while three predict the variant creates or strengthens an in-frame cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The ENIGMA Consortium recommends a reduced PVS1 evidence strength (PVS1_supporting) for variants altering this splice site, as they may result in functional in-frame transcripts that could rescue gene functionality. The variant allele was found at a frequency of 4e-06 in 251404 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.442-1G>T has been reported in the literature in a study of patients with breast and/or ovarian cancer without strong evidence of causality (Bhaskaran_2019). This report does 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. ClinVar contains an entry for this variant (Variation ID: 462651). Six submitters have classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Dec 14, 2021)
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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: SCV001184199.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.442-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 6 of the BRCA1 gene. This nucleotide position … (more)
The c.442-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 6 of the BRCA1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Canonical splice site variants are typically considered deleterious; however, alterations at this particular splice acceptor site result in a transcript with a predicted in-frame loss of a single amino acid at the beginning of coding exon 6 (Ambry internal data; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38). This single amino acid loss is a naturally occurring isoform and may be referred to as Δ8p in some literature (Colombo M et al. Hum Mol Genet., 2014 Jul;23:3666-80). The functional and clinical significance of this single amino acid loss is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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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Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients. | Bhaskaran SP | International journal of cancer | 2019 | PMID: 30702160 |
Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. | Colombo M | Human molecular genetics | 2014 | PMID: 24569164 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs1351019392 ...
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.