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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 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no 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
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)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer
Identifiers:
MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000043189Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq
no assertion criteria provided
pathogenic
(Jul 13, 2012)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

SCV000077108Invitae
criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))
Pathogenic
(Jan 12, 2018)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000271311Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine)
criteria provided, single submitter

(LMM Criteria)
Pathogenic
(Jan 10, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000403078Illumina Clinical Services Laboratory,Illumina
criteria provided, single submitter

(ICSL Variant Classification 20161018)
Pathogenic
(Jun 14, 2016)
germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000586860Cancer 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)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000587006Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)
no assertion criteria provided
Pathogenic
(Jan 31, 2014)
germlineresearch

SCV000588022Department 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)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000591232Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000699291Integrated Genetics/Laboratory Corporation of America
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Aug 10, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing, research
not providedgermlinenot provided1111not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Ashkenazi Jewishgermlineno1not providednot provided572not providedresearch

Citations

PubMed

Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.

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.

PubMed [citation]
PMID:
22703879
PMCID:
PMC3397257

High prevalence of BRCA1 and BRCA2 germline mutations with loss of heterozygosity in a series of resected pancreatic adenocarcinoma and other neoplastic lesions.

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.

PubMed [citation]
PMID:
23658460
PMCID:
PMC3959126
See all PubMed Citations (22)

Details of each submission

From Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq, SCV000043189.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Ashkenazi Jewish1not providednot providedresearch 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineno572not provideddiscovery1not providednot providednot provided

From Invitae, SCV000077108.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), SCV000271311.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided11not providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided11not provided11not provided

From Illumina Clinical Services Laboratory,Illumina, SCV000403078.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR), SCV000586860.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587006.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR), SCV000588022.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591232.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Integrated Genetics/Laboratory Corporation of America, SCV000699291.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 30, 2018