ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.442-22_442-13del
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.442-22_442-13del
Variation ID: 246362 Accession: VCV000246362.19
- Type and length
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Deletion, 10 bp
- Location
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Cytogenetic: 17q21.31 17: 43099893-43099902 (GRCh38) [ NCBI UCSC ] 17: 41251910-41251919 (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 25, 2016 Jun 17, 2024 Jun 11, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:43099892:GTAAAGAACAGT:GT
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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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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13037 | 14843 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2019 | RCV000235873.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 25, 2023 | RCV000463705.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 11, 2023 | RCV001189625.15 | |
Pathogenic (1) |
reviewed by expert panel
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Jun 11, 2024 | RCV004567784.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Pathogenic
(Jun 11, 2024)
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reviewed by expert panel
Method: curation
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BRCA1-related cancer predisposition
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004101415.3 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024 |
Comment:
The c.442-22_442-13del variant is an intronic variant occurring in intron 6 of the BRCA1 gene. This deletion variant was not observed in gnomAD v2.1 (exomes … (more)
The c.442-22_442-13del variant is an intronic variant occurring in intron 6 of the BRCA1 gene. This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and qPCR assays demonstrated that the variant impacts splicing by activation of a cryptic acceptor site, resulting in a 59nt intron retention of intron 6. Combination of non-allele specific assay results (PMIDs: 10323242, 32745242) and assessment of full-length transcript quantification by real-time PCR in carriers (personal communication) suggests a near complete splicing effect. Appropriate code strength determined by comparison of results to PVS1 decision tree and assessment of mRNA splicing data (PVS1_Strong (RNA) met). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 48.83, within the thresholds for strong pathogenic evidence (LR >18.7 & <=350) (PP1_Strong met; PMID: 32745242, Internal lab contributors). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 4.83 (based on Pathology LR=4.83), within the thresholds for Moderate evidence towards pathogenicity (LR >4.3 & <=18.7) (PP4_Moderate met; 32745242, Internal lab contributors). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1_Strong (RNA), PP1_Strong, PP4_Moderate). (less)
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary Breast and Ovarian Cancer
Affected status: yes
Allele origin:
germline
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Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV000897861.1
First in ClinVar: Apr 17, 2019 Last updated: Apr 17, 2019 |
Comment:
Data used in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing. Denominator ~16,600. In the GNOMAD NFE population of … (more)
Data used in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing. Denominator ~16,600. In the GNOMAD NFE population of 63,369 individuals, the frequency of this variant is 0. exact: p=0.04. (PS4_strong) This variant is reported twice on ClinVar. There are additional reports of this variant in: i) Li et al. 1999 Hum Genet 104 201-204: Variant found variant in 2 unrelated Taiwanese families:Br Ca in mother and daughter (age 58 & 28), Br Ca/Ov Ca in mother age 48 and Br Ca in daughter (age 30). ii) Ang et al Cancer Epidem Bio and Prev 2007; 16 (11) two affected sisters. In the remainder of the GNOMAD populations (75,263 individuals, including 8624 East Asians), the frequency of this variant is 0 (PM2). Li et al. 1999 Hum Genet 104 201-204: RT-PCR carried out: an insertion of 59 nucleotides mRNA results in frameshift and premature termination codon in exon 8 (historical exon numbering). AND Ang et al Cancer Epidem Bio and Prev 2007; 16 (11): insertion of 59 nucleotides mRNA. However, only single WT control used. (PS3_mod) Data not included in classification: Li et al. 1999 Hum Genet 104 201-204: variant segregates with disease in two 2 case families. In silico analysis predict effect on splicing: Predicted change at acceptor site 13 bps downstream. MaxEnt: -43.6%; NNSPLICE: -65.0% Other information: Wong et al. 2015 (PLOS1). Patient had a BRCA1 c.442-22-442-13 variant and also a pathogenic variant in BRCA2 c.5645C>A; p.Ser1882*). (less)
Number of individuals with the variant: 2
Sex: female
Geographic origin: United Kingdom
Testing laboratory: UK Molecular Diagnostic Labs
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Likely pathogenic
(Dec 12, 2019)
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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: SCV000293883.9
First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016 |
Comment:
Non-canonical splice site variant demonstrated to result in the insertion of 59 nucleotides, leading to protein truncation or nonsense mediated decay in a gene for … (more)
Non-canonical splice site variant demonstrated to result in the insertion of 59 nucleotides, leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Li 1999, Ang 2007); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Li 1999, Ang 2007, Lin 2016); Not observed in large population cohorts (Lek 2016); Also known as 561-22_561-13del10 or IVS7-22_IVS7-13del10; This variant is associated with the following publications: (PMID: 26824983, 10323242, 18006916) (less)
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Pathogenic
(Sep 11, 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: SCV001356943.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes a 10 nucleotide deletion near the splice acceptor site in intron 6 of the BRCA1 gene. Splice site prediction tools predict that … (more)
This variant causes a 10 nucleotide deletion near the splice acceptor site in intron 6 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies on carrier-derived RNA has shown an out-of-frame splicing associated with variant (PMID: 10323242, 18006916, 32745242). Moreover, cellular characterization on ex vivo cells derived from carriers showed sensitivity to PARP inhibitor and other cellular features consistent with compromised BRCA1 function in the normal cellular response to DNA damage and DNA replication blockage (32745242). This variant has been reported in over 10 individuals affected with breast and/or ovarian cancer (PMID: 10323242, 18006916, 26824983, 32745242, 34503154), and a haplotype analysis suggests that this variant may be founder mutation among Han Chinese (PMID: 32745242). This variant also has been reported to segregate with breast and ovarian cancers in at least five carrier families (PMID: 10323242, 32745242). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Aug 25, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000549418.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the BRCA1 gene. It does not … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10323242, 18006916, 26221963, 26824983; Invitae). It is commonly reported in individuals of Asian ancestry (PMID: 10323242, 18006916, 26221963, 26824983; Invitae). This variant is also known as IVS7-15del10, IVS7-22del10, and g.41251910_41251919 delGTAAAGAACA. ClinVar contains an entry for this variant (Variation ID: 246362). Studies have shown that this variant results in insertion of 59 bp in intron 7 and introduces a premature termination codon (PMID: 10323242, 18006916). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 11, 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: SCV002631167.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.442-22_442-13del10 intronic pathogenic mutation, located in intron 5 of the BRCA1 gene, results from a deletion of 10 nucleotides within intron 5 of the … (more)
The c.442-22_442-13del10 intronic pathogenic mutation, located in intron 5 of the BRCA1 gene, results from a deletion of 10 nucleotides within intron 5 of the BRCA1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. This alteration is identified in numerous individuals with a clinical history of breast and/or ovarian cancer who are of Chinese descent and it segregates with disease in multiple families (Lin PH et al. Oncotarget, 2016 Feb;7:8310-20; Wong ES et al. PLoS One, 2015 Jul;10:e0134408; Ang P et al. Cancer Epidemiol Biomarkers Prev, 2007 Nov;16:2276-84; Li SS et al. Hum Genet, 1999 Mar;104:201-4). This alteration leads to the use of a cryptic acceptor site within intron 5 leading to a partial inclusion of this intron and a protein with a premature termination codon (Ambry internal data; Li SS et al. Hum Genet, 1999 Mar;104:201-4; Ang P et al. Cancer Epidemiol Biomarkers Prev, 2007 Nov;16:2276-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (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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Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study. | Chandrasekaran D | Cancers | 2021 | PMID: 34503154 |
Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore. | Shaw T | International journal of cancer | 2021 | PMID: 32745242 |
Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer. | Lin PH | Oncotarget | 2016 | PMID: 26824983 |
Predictive Factors for BRCA1 and BRCA2 Genetic Testing in an Asian Clinic-Based Population. | Wong ES | PloS one | 2015 | PMID: 26221963 |
BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy. | Ang P | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2007 | PMID: 18006916 |
Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in Taiwan. | Li SS | Human genetics | 1999 | PMID: 10323242 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/476a47b3-617d-44fa-a8d1-155d588f2b48 | - | - | - | - |
Text-mined citations for rs879254224 ...
HelpRecord last updated Oct 13, 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.