- This record was updated by the submitter. Please see the current version.
NM_007294.3(BRCA1):c.68_69delAG (p.Glu23Valfs) AND Hereditary breast and ovarian cancer syndrome
- Germline classification:
- Pathogenic (9 submissions)
- Last evaluated:
- Jan 12, 2018
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000034761.14
Allele description
NM_007294.3(BRCA1):c.68_69delAG (p.Glu23Valfs)
- Gene:
- BRCA1:BRCA1, DNA repair associated [Gene - OMIM - HGNC]
- Variant type:
- Deletion
- Cytogenetic location:
- 17q21.31
- Genomic location:
- Preferred name:
- NM_007294.3(BRCA1):c.68_69delAG (p.Glu23Valfs)
- Other names:
- 185_186delAG
- HGVS:
- NC_000017.11:g.43124030_43124031delCT
- NG_005905.2:g.93955_93956delAG
- NM_007294.3:c.68_69delAG
- NM_007297.3:c.-20_-19delAG
- NM_007299.3:c.66_67delAG
- NM_007300.3:c.66_67delAG
- NP_009225.1:p.Glu23Valfs
- NP_009230.2:p.Glu23Valfs
- NP_009231.2:p.Glu23Valfs
- LRG_292t1:c.68_69delAG
- LRG_292:g.93955_93956delAG
- LRG_292p1:p.Glu23Valfs
- NC_000017.10:g.41276045_41276046delCT
- NC_000017.10:g.41276047_41276048delCT
- NC_000017.11:g.43124028_43124029delCT
- NG_005905.2:g.93953_93954delAG
- NM_007294.3:c.66_67del
- NM_007294.3:c.66_67delAG
- NM_007294.3:c.68_69del
- NM_007297.3:c.-22_-21delAG
- NM_007299.3:c.68_69delAG
- NR_027676.1:n.227_228delAG
- NR_027676.1:n.229_230delAG
- U14680.1:c.66_67delAG
- U14680.1:n.185_186delAG
- p.E23VFS*17
- p.E23VfsX17
- p.Glu23Valfs*17
- p.Glu23ValfsX17
- p.Glu23fs
- NM_007294.3(BRCA1):c.68_69delAG
- NM_007294.3:c.68_69delAG(185delAG or 187delAG)
- NR_027676.1:c.229_230delAG
This HGVS expression did not pass validation- Nucleotide change:
- 185delAG
- Links:
- Breast Cancer Information Core (BIC) (BRCA1): 185&base_change=del AG; OMIM: 113705.0003; dbSNP: rs386833395; dbSNP: rs80357783
- NCBI 1000 Genomes Browser:
- rs386833395
- Allele Frequency:
- 0.00024(-)
- Molecular consequence:
- NM_007297.3:c.-20_-19delAG - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
- NM_007294.3:c.68_69delAG - frameshift variant - [Sequence Ontology: SO:0001589]
- NR_027676.1:n.229_230delAG - non-coding transcript variant - [Sequence Ontology: SO:0001619]
- Functional consequence:
- loss_of_function_variant [Sequence Ontology: SO:0002054]
- Observations:
- 11
Condition(s)
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000043189 | Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq | no assertion criteria provided | pathogenic (Jul 13, 2012) | germline | research | |
SCV000077108 | Invitae | criteria provided, single submitter (Nykamp K et al. (Genet Med 2017)) | Pathogenic (Jan 12, 2018) | germline | clinical testing | |
SCV000271311 | Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine) | criteria provided, single submitter (LMM Criteria) | Pathogenic (Jan 10, 2018) | germline | clinical testing | |
SCV000403078 | Illumina Clinical Services Laboratory,Illumina | criteria provided, single submitter (ICSL Variant Classification 20161018) | Pathogenic (Jun 14, 2016) | germline | clinical testing | PubMed (13) ICSL_Variant_Classification_20161018.pdf, |
SCV000586860 | Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR) | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Apr 18, 2017) | germline | clinical testing | |
SCV000587006 | Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR) | no assertion criteria provided | Pathogenic (Jan 31, 2014) | germline | research | |
SCV000588022 | Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR) | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Apr 20, 2017) | germline | clinical testing | |
SCV000591232 | Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR) | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
SCV000699291 | Integrated Genetics/Laboratory Corporation of America | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Aug 10, 2017) | germline | clinical testing | PubMed (2) LabCorp Variant Classification Summary - May 2015.docx |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing, research |
not provided | germline | not provided | 11 | 11 | not provided | not provided | not provided | clinical testing |
not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
Ashkenazi Jewish | germline | no | 1 | not provided | not provided | 572 | not provided | research |
Citations
PubMed
Johnston JJ, Rubinstein WS, Facio FM, Ng D, Singh LN, Teer JK, Mullikin JC, Biesecker LG.
Am J Hum Genet. 2012 Jul 13;91(1):97-108. doi: 10.1016/j.ajhg.2012.05.021. Epub 2012 Jun 14.
- PMID:
- 22703879
- PMCID:
- PMC3397257
Lucas AL, Shakya R, Lipsyc MD, Mitchel EB, Kumar S, Hwang C, Deng L, Devoe C, Chabot JA, Szabolcs M, Ludwig T, Chung WK, Frucht H.
Clin Cancer Res. 2013 Jul 1;19(13):3396-403. doi: 10.1158/1078-0432.CCR-12-3020. Epub 2013 May 8.
- PMID:
- 23658460
- PMCID:
- PMC3959126
Details of each submission
From Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq, SCV000043189.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | Ashkenazi Jewish | 1 | not provided | not provided | research | PubMed (1) |
Description
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See PubMed ID:22703879 for details.
Description
Converted during submission to Pathogenic.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | no | 572 | not provided | discovery | 1 | not provided | not provided | not provided |
From Invitae, SCV000077108.10
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (9) |
Description
This sequence change deletes two nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift at codon 23. This creates a premature translational stop signal (p.Glu23Valfs*17) and is expected to result in an absent or disrupted protein product. This pathogenic variant is a known common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266), although it has been observed in individuals from other ethnicities (PMID: 8651293, 8571953, 9921907). This variant has also been reported in individuals affected with pancreatic cancer (PMID: 15994883, 22430266, 23658460, 24737347). It is also known as 185delAG or 187delAG in the literature. This variant has been associated with a 64% to 83% risk of breast cancer by age 70, and a 14% to 58% risk of ovarian cancer by age 70 (PMID: 15994883, 22430266). For these reasons, this variant has been classified as Pathogenic.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), SCV000271311.3
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 11 | not provided | not provided | clinical testing | PubMed (1) |
Description
The p.Glu23fs variant in BRCA1 has been reported in numerous individuals with hereditary breast and ovarian cancer (HBOC) and is a known pathogenic Ashkenazi Jewish founder variant. It has also been identified in 38/10150 Ashkenazi Jewish and 11/126308 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80357914). Please note that this frequency is low enough to be consistent with the frequency of HBOC in the general population. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 23 and lead to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in HBOC. Additionally, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282348.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PS4_strong (Richards 2015).
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | 11 | not provided | 11 | not provided |
From Illumina Clinical Services Laboratory,Illumina, SCV000403078.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (13) |
Description
The c.68_69delAG (p.Glu23ValfsTer17) variant, also commonly known as 185delAG, is a frameshift variant that is very well described in the literature as one of the most frequent variants found in breast cancer (Shattuck-Eidens et al. 1995; Offit et al. 1996). It was first identified in a study by Simard et al. (1994) in index cases from four unrelated Canadian families with hereditary breast and ovarian cancer (HBOC). Wang et al. (2012) conducted a meta-analysis of over 29 studies published between 2000 and 2010 and determined the overall frequency of the p.Glu23ValfsTer17 variant in 2128 breast cancer cases to be 0.072. The variant is one of three known common founder germline variants primarily found in individuals of Ashkenazi Jewish heritage (Struewing et al. 1997; Abeliovich et al. 1997; Laitman et al. 2013) and has been detected in 20% of Ashkenazi Jewish women diagnosed with breast cancer before age 42 years (Offit et al 1996). In the Ashkenazi Jewish population, the variant is associated with a risk of between 56% and 83% of breast cancer and of between 14% and 58% risk of ovarian cancer by the age of 70 (Struewing et al. 1997; Antoniou et al. 2005; Finkelman et al. 2012). The variant has been observed in individuals of other ethnicities (Wang et al. 2012; Laitman et al. 2013). The variant is reported at a frequency of 0.00042 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the available evidence, the p.Glu23ValfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR), SCV000586860.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587006.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR), SCV000588022.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591232.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Integrated Genetics/Laboratory Corporation of America, SCV000699291.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
Variant summary: The BRCA1 c.68_69delAG (p.Glu23Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is one of the most common Jewish founder mutations. Multiple publications have cited the variant in affected individuals. This variant was found in 29/120972 control chromosomes at a frequency of 0.0002397, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Sep 30, 2018