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rs80357914

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_007294.4(BRCA1):c.68_69del(p.Glu23ValfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,612,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E23E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:71O:4

Conservation

PhyloP100: 3.57
Variant links:
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 3469 pathogenic variants in the truncated region.
PP5
Variant 17-43124027-ACT-A is Pathogenic according to our data. Variant chr17-43124027-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 17662.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43124027-ACT-A is described in Lovd as [Likely_pathogenic]. Variant chr17-43124027-ACT-A is described in Lovd as [Pathogenic]. Variant chr17-43124027-ACT-A is described in Lovd as [Pathogenic]. Variant chr17-43124027-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.68_69del p.Glu23ValfsTer17 frameshift_variant 2/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.68_69del p.Glu23ValfsTer17 frameshift_variant 2/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00548
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000227
AC:
57
AN:
251050
Hom.:
0
AF XY:
0.000251
AC XY:
34
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00407
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000970
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000116
AC:
169
AN:
1459934
Hom.:
0
AF XY:
0.000142
AC XY:
103
AN XY:
726416
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00398
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.000332
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00548
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000651
Hom.:
0
Bravo
AF:
0.000125
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:71Other:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:27Other:1
Pathogenic, criteria provided, single submitterclinical testingMolecular Endocrinology Laboratory, Christian Medical College-- -
Pathogenic, criteria provided, single submitterclinical testingGreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited-- -
Pathogenic, no assertion criteria providedclinical testingPathway GenomicsJul 24, 2014- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Molecular Diagnostics, Institute of Oncology LjubljanaApr 02, 2020- -
Pathogenic, no assertion criteria providedclinical testingBRCAlab, Lund UniversityAug 26, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesDec 03, 2017- -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterAug 09, 2022The c.68_69del variant in BRCA1 (also referred as c.185delAG) is an established pathogenic variant [ClinVar ID:17662] that is predicted (p.(Glu23fs)) to result in atruncated or absent BRCA1 protein due to nonsense mediated decay. The c.68_69del variant is a founder mutation in Ashkenazi Jewish population with a frequency of about 1% [PMID: 14576434]. The c.68_69del variant has been reported in multiple individuals with breast and/or ovarian, prostate, and pancreatic cancers [PMID:14576434, 20711688, 22516946, 23633455, 22752604]. Based on available evidence, this c.68_69del (p.(Glu23fs)) variant identified in BRCA1 is reported as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganNov 03, 2014- -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2008- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Medical Genetics, Oslo University HospitalJul 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testingUniversity of Washington Department of Laboratory Medicine, University of WashingtonNov 20, 2015- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpreted as Pathogenic and reported on 12-11-2018 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyJan 22, 2019- -
Pathogenic, criteria provided, single submitterliterature onlyCounsylMay 30, 2014- -
Pathogenic, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Nov 14, 2013- -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineMay 25, 2017The c.68_69del (p.Glu23Valfs*17) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 14576434, 26718727, 21503673, 22430266, 23633455, 22752604, referred as c.185delAG in some publications]. This variant is a founder mutation in Ashkenazi Jews with a frequency of about 1% [PMID 14576434]. The variant has also been detected in patients with prostate [PMID 22516946] and pancreatic cancer [PMID 20711688, 24737347, 23658460, 26440929]. This one bp deletion in exon 2 results in a frameshift and the creation of a premature stop codon. Functional in vitro assays showed that this variant was deleterious [PMID 23867111]. This variant has been reported in 31 individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This variant is thus classified as pathogenic -
Pathogenic, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 02, 2016- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Pathogenic, no assertion criteria providedclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterMay 05, 2023This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later – p.Glu23Valfs*17). This is expected to result in an absent or disrupted protein product. This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662). Therefore, this variant has been classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGenologica MedicaJan 01, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJun 17, 2022- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The frameshift deletion p.E23Vfs*17 in BRCA1 (NM_007294.3) has been reported previously in affected patients (Laitman Y et al). The variant is present in 0.40% in indiviudals from the Ashkenazi Jewish background. It is a common founder mutation in the Ashkenazi Jew community. It has been classified as Pathogenic in the ClinVar database by the expert review panel. The p.E23Vfs*17 variant is a loss of function variant in the gene BRCA1. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panelcurationClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGenOct 08, 2023The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 17 of the frameshift, or amino acid 39 (p.Glu23ValfsTer17). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 3 (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 32546644) (PS3 met). In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PS3). -
Pathogenic, criteria provided, single submitterclinical testingDASAMar 05, 2022The c.68_69del;p.(Glu23Valfs*17) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17662; PMID: 7611277; PMID: 7894492; PMID: 14576434; PMID: 21503673; PMID: 22430266)PS4. The variant is present at low allele frequencies population databases (rs80357914 – gnomAD 0.001446%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingConsortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of CambridgeOct 02, 2015- -
Pathogenic, criteria provided, single submitterclinical testingBioinformatics dept., Datar Cancer Genetics Limited, IndiaJul 14, 2017- -
not provided Pathogenic:14
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 09, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 16, 2019Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 185delAG or 187delAG; This variant is associated with the following publications: (PMID: 18594935, 26071757, 26221963, 27259235, 28049106, 26822237, 29176636, 31948886, 22703879, 22535016, 22516946, 22009639, 23633455, 23658460, 22763381, 23086583, 19906413, 21503673, 22430266, 20711688, 22752604, 22006311, 7611277, 23867111, 25556971, 24737347, 26440929, 26689913, 26641009, 27553291, 23788959, 26718727, 26681312, 27836010, 29321669, 27062684, 28528518, 11802208, 28477318, 29339979, 29752822, 28324225, 27989354, 29907814, 29431110, 29560538, 26556299, 10464624, 29470806, 28390335, 28993434, 26357657, 29161300, 30702160, 30067863, 30152102, 30630528, 30122538, 30186769, 30720243, 30322717, 30093976, 31159747, 30113427, 31372034, 30489631, 30612635, 31454914, 31528241, 29625052, 31447099, 31980526, 34308366, 33646313, 10739756, 10733239, 11597388, 9042909, 12220453, 31589614, 32341426, 9634504, 10885601, 32719484, 33556450, 12491828, 32338768, 30875412, 30787465, 16030426, 33224455) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalJun 05, 2014- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024BRCA1: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 27, 2023The BRCA1 c.68_69delAG; p.Glu23ValfsTer17 variant (rs386833395), also known as 185delAG, is a well known founder variant associated with breast, ovarian, and pancreatic cancer in the Ashkenazi Jewish population as well as other ethnic populations (Abeliovich 1997, Antoniou 2005, King 2003, Laitman 2019, Lucas 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17662), and is found in the general population with an overall allele frequency of 0.02% (58/282442 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Glu23ValfsTer17 variant is considered to be pathogenic. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. Antoniou AC et al. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005 Jul;42(7):602-3. King MC et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003 Oct 24;302(5645):643-6. Laitman Y et al. The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries. Hum Mutat. 2019 Nov;40(11):e1-e23. Lucas AL et al. BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer. 2014 Jul 1;120(13):1960-7. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 06, 2020- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 24, 2023- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 09, 2023This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0041 (42/10368 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as one of the common pathogenic BRCA founder variants in the Ashkenazi Jewish population (PMIDs: 22430266 (2012), 14576434 (2003), 8841191 (1996), 7550349 (1995)). The variant has been reported in individuals from multiple populations with a personal or family history of breast and/or ovarian cancer (PMIDs: 35377489 (2022), 33758026 (2022), 35039532 (2022), 35264596 (2022), 35356428 (2022), 35710434 (2022), 33646313 (2021), 32341426 (2020), 31528241 (2019), 31372034 (2019), 31159747 (2019), 30875412 (2019), 30630528 (2019), 30489631 (2019)) and prostate cancer (PMIDs: 33556450 (2021), 32338768 (2020), 31948886 (2020)). Functional studies report the variant disrupts proper protein function (PMID: 35459234 (2022)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Hereditary breast ovarian cancer syndrome Pathogenic:12Other:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change creates a premature translational stop signal (p.Glu23Valfs*17) 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 present in population databases (rs386833395, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, and pancreatic cancer (PMID: 9042909, 15994883, 22430266, 23658460, 24737347). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8571953, 8651293, 9042909, 9921907, 15994883, 22430266, 23658460, 24737347). This variant is also known as 185delAG or 187delAG. ClinVar contains an entry for this variant (Variation ID: 17662). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification providedliterature onlyGeneReviews-Founder variant in Ashkenazi Jews; accounts for 72% of pathogenic variants in this population -
Pathogenic, no assertion criteria providedclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 10, 2017Variant 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. -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by Lab Invitae. Variant interpreted as Pathogenic and reported, most recently, on 02-06-2021 and on 03-26-2018. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Pathology and Molecular Medicine, Queen's UniversityApr 20, 2017- -
Pathogenic, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Pathogenic, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCancer Genetics and Genomics Laboratory, British Columbia Cancer AgencyApr 18, 2017- -
Pathogenic, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoJan 31, 2014- -
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalMar 22, 2022The BRCA1 c.68_69del (p.Glu23ValfsTer17) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.41% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/17-41276044-ACT-A?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 14576434, 26718727, 21503673, 22430266, 23633455, 22752604), prostate (PMID: 22516946) and pancreatic cancer (PMID: 20711688, 24737347, 23658460, 26440929). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 185delAG or 187delAG in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 01, 2020The p.Glu23ValfsX17 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 (Struewing 1997 PMID: 9145676, Abeliovich 2013 PMID: 9042909). It has also been identified in 0.4% (42/10368) of Ashkenazi Jewish and 0.009% (11/128780) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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 individuals with 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. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016The 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. -
Familial cancer of breast Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJun 22, 2023Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJan 01, 2020This sequence change deletes 2 nucleotides from exon 2 of the BRCA1 mRNA (c.68_69delAG), causing a frameshift after codon 23 and the creation of a premature translation stop signal 17 amino acid residues later - p.(Glu23Valfs*17). This is expected to result in an absent or disrupted protein product.This variant, also known as BRCA1_185delAG or 187delAG, is one of three main pathogenic founder variants in the Ashkenazi Jewish population although it has been observed in individuals from other ethnicities as well (PMID: 23199084 ). This mutation has been described in the mutation database ClinVar(Variation ID: 17662). -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2017- -
Pathogenic, criteria provided, single submitterresearchDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDec 15, 2020- -
Hereditary cancer-predisposing syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 17, 2022The c.68_69delAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 68 to 69, causing a translational frameshift with a predicted alternate stop codon (p.E23Vfs*17). This alteration is one of three well-characterized Ashkenazi Jewish founder mutations, with an overall carrier frequency of nearly 1% in this population (Struewing JP et al. Nat. Genet. 1995 Oct;11:198-200; Schubert EL et al. Genet Test, 1997;1:41-6; Hartge P et al. Am. J. Hum. Genet. 1999 Apr;64:963-70). This germline mutation has been reported in individuals of Ashkenazi Jewish descent, as well as in cohorts of other ethnicities, with hereditary breast and ovarian cancer (HBOC) syndrome, including individuals with male breast cancer, pancreatic cancer, and prostate cancer (Antoniou AC et al. J. Med. Genet. 2005 Jul;42:602-3; Lucas AL et al. Clin. Cancer Res. 2013 Jul;19:3396-403; Lucas AL et al. Cancer. 2014 Jul;120:1960-7; Bernards SS et al. Gynecol Oncol, 2016 Feb;140:221-5; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Na R et al. Eur Urol, 2017 05;71:740-747; Gabald&oacute; Barrios X et al. Fam. Cancer. 2017 Oct;16:477-489; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Schayek H et al. Breast Cancer Res Treat, 2018 Jul;170:399-404; Brand R et al. Cancer, 2018 09;124:3520-3527; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Wen WX et al. J Med Genet, 2018 02;55:97-103; Cock-Rada AM et al. Fam Cancer, 2018 01;17:23-30; Mehta A et al. Cancer Manag Res, 2018 Nov;10:6505-6516; Li JY et al. Int J Cancer, 2019 01;144:281-289; Abe T et al. J Clin Oncol, 2019 05;37:1070-1080; Ashour M et al. Cancer Manag Res, 2019 Jul;11:6275-6284). In a large case control-study, this variant was reported in 30/60,466 breast cancer cases and in 8/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 185delAG, 187delAG, and 189delAG 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. -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.May 23, 2018- -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 13, 2023This variant deletes 2 nucleotides in exon 2 of the BRCA1 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 185delAG and 187delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.96-1.14% minor allele frequency (PMID: 7550349, 8571953, 30152102). This variant has been reported in dozens of individuals and families affected with breast and ovarian cancer (PMID: 7894492, 7611277, 7837387, 8533757, 8531968, 8642955, 9042909, 9150153, 21643751, 30480775, 35020120). This variant also has been observed in individuals from diverse ethnicities in Africa, America, Asia and Europe (PMID: 8651293, 24312913). The risk of female breast cancer among carriers of this mutation is 55-83% by age 70, and the risk of ovarian cancer is 12-58% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has detected this variant in 30/60436 cases and 8/53453 unaffected individuals with an odds ratio (OR) of 3.317 (95%CI 1.52 to 7.235) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001114). This variant has been identified in 58/282442 chromosomes (42/10368 Ashkenazi Jewish chromosomes) 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. -
Pathogenic, criteria provided, single submittercurationSema4, Sema4Oct 07, 2021- -
Breast and/or ovarian cancer Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingFoulkes Cancer Genetics LDI, Lady Davis Institute for Medical ResearchJun 22, 2016- -
Pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumJun 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMar 04, 2022- -
BRCA1-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 16, 2024The BRCA1 c.68_69delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu23Valfs*17). This variant, also described as 185delAG or 187delAG in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #604370). This is a recurrent variant among individuals of Spanish origin and is a founder variant in the Ashkenazi Jewish population, identified in about 1% of Ashkenazi Jewish individuals unselected for breast cancer (Gabaldó Barrios et al. 2017. PubMed ID: 28477318; Finkelman et al. 2012. PubMed ID: 22430266; Struewing et al. 1997. PubMed ID:9145676; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomad. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/). In summary, this variant is interpreted as pathogenic. -
Invasive medullary breast carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited-- -
Triple-negative breast cancer Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingCancer Genomics Lab, PINUM Cancer HospitalMar 11, 2023- -
Neoplasm of ovary Pathogenic:1
Pathogenic, no assertion criteria providedresearchGerman Consortium for Hereditary Breast and Ovarian Cancer, University Hospital CologneDec 01, 2018- -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 04, 2022- -
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The p.Glu23ValfsX17 deletion variant is one of three known founder pathogenic mutations common to individuals of Ashkenazi Jewish descent (Petrucelli 1998). This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 23 and leads to a premature stop codon 17 codons downstream. This alteration is then predicted to lead to a truncated or absent protein product and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -
Endometrial carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumFeb 21, 2023- -
Pancreatic cancer, susceptibility to, 4 Other:1
risk factor, no assertion criteria providedliterature onlyOMIMOct 01, 2008- -

Computational scores

Source: dbNSFP v4.3

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Splicing

Name
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SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80357914; hg19: chr17-41276044; API