Variant allele predicted to encode a truncated non-functional protein.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.68_69dup (p.Cys24fs)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2016 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.68_69dup (p.Cys24fs)
Variation ID: 55667 Accession: VCV000055667.20
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 17q21.31 17: 43124027-43124028 (GRCh38) [ NCBI UCSC ] 17: 41276044-41276045 (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 Jun 17, 2024 Sep 8, 2016 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- C24fs
- Other names
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188insAG
- Canonical SPDI
- NC_000017.11:43124027:CTCT:CTCTCT
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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.
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The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00023
Exome Aggregation Consortium (ExAC) 0.00024
- Links
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. |
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| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13050 | 14856 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
reviewed by expert panel
|
Sep 8, 2016 | RCV000143834.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 11, 2020 | RCV000223371.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 24, 2023 | RCV000779878.15 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 30, 2019 | RCV000657219.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2022 | RCV002504947.8 |
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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|---|---|---|---|---|---|
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Pathogenic
(Sep 08, 2016)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000299398.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Feb 10, 2017)
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criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000778945.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Comment:
This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this … (more)
This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 187_188dupAG or 69_70insAG. The normal sequence, with the bases that are duplicated in brackets, is TTAG[dupAG]TGTC. The duplication causes a frameshift which changes a Cysteine to a Serine at codon 24, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.68_69dupAG has been published in association with at least three cases of breast cancer (Borg 2010, Dean 2015). We consider this variant to be pathogenic. (less)
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Pathogenic
(May 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916757.2
First in ClinVar: Jun 02, 2019 Last updated: Nov 08, 2019 |
Comment:
Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251050 control chromosomes (gnomAD). c.68_69dupAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Dean_2015, Judkins_2005, Quezada Urban_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 24, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001584844.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys24Serfs*8) in the BRCA1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys24Serfs*8) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 55667). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 17, 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
|
Baylor Genetics
Accession: SCV004215148.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Apr 10, 2022)
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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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813509.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 30, 2019)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296302.4
First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024 |
Comment:
The BRCA1 c.68_69dup (p.Cys24Serfs*8) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant … (more)
The BRCA1 c.68_69dup (p.Cys24Serfs*8) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 26543556 (2015), and 30262796 (2018)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Sep 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273758.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.68_69dupAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of AG at nucleotide position 68, causing a … (more)
The c.68_69dupAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of AG at nucleotide position 68, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*8). This alteration has been reported in several breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Dean M et al. Gigascience, 2015 Nov;4:50; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Of note, this alteration is also designated as 188insAG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 25, 2011)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000115151.3
First in ClinVar: Feb 09, 2014 Last updated: Sep 27, 2014 |
|
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Pathogenic
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144175.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 2
Ethnicity/Population group: Latin American, Caribbean
|
Comment:
Comment:
This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 187_188dupAG or 69_70insAG. The normal sequence, with the bases that are duplicated in brackets, is TTAG[dupAG]TGTC. The duplication causes a frameshift which changes a Cysteine to a Serine at codon 24, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.68_69dupAG has been published in association with at least three cases of breast cancer (Borg 2010, Dean 2015). We consider this variant to be pathogenic.
Comment:
Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251050 control chromosomes (gnomAD). c.68_69dupAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Dean_2015, Judkins_2005, Quezada Urban_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Cys24Serfs*8) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 55667). For these reasons, this variant has been classified as Pathogenic.
Comment:
The BRCA1 c.68_69dup (p.Cys24Serfs*8) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 26543556 (2015), and 30262796 (2018)). Based on the available information, this variant is classified as pathogenic.
Comment:
The c.68_69dupAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of AG at nucleotide position 68, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*8). This alteration has been reported in several breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Dean M et al. Gigascience, 2015 Nov;4:50; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Of note, this alteration is also designated as 188insAG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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. |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
Comment:
This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 187_188dupAG or 69_70insAG. The normal sequence, with the bases that are duplicated in brackets, is TTAG[dupAG]TGTC. The duplication causes a frameshift which changes a Cysteine to a Serine at codon 24, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.68_69dupAG has been published in association with at least three cases of breast cancer (Borg 2010, Dean 2015). We consider this variant to be pathogenic.
Comment:
Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251050 control chromosomes (gnomAD). c.68_69dupAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Dean_2015, Judkins_2005, Quezada Urban_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Cys24Serfs*8) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 55667). For these reasons, this variant has been classified as Pathogenic.
Comment:
The BRCA1 c.68_69dup (p.Cys24Serfs*8) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 26543556 (2015), and 30262796 (2018)). Based on the available information, this variant is classified as pathogenic.
Comment:
The c.68_69dupAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of AG at nucleotide position 68, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*8). This alteration has been reported in several breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Dean M et al. Gigascience, 2015 Nov;4:50; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Of note, this alteration is also designated as 188insAG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Multi-Center Study of BRCA1 and BRCA2 Germline Mutations in Mexican-Mestizo Breast Cancer Families Reveals Mutations Unreported in Latin American Population. | Millan Catalan O | Cancers | 2019 | PMID: 31454914 |
| Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility. | Quezada Urban R | Cancers | 2018 | PMID: 30262796 |
| Addressing health disparities in Hispanic breast cancer: accurate and inexpensive sequencing of BRCA1 and BRCA2. | Dean M | GigaScience | 2015 | PMID: 26543556 |
| 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 |
| 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 |
Text-mined citations for rs80357914 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.