ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.68_69del (p.Glu23fs)

dbSNP: rs80357914
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Total submissions: 78
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen RCV004566751 SCV004101425 pathogenic BRCA1-related cancer predisposition 2024-06-11 reviewed by expert panel curation The 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).
Invitae RCV000034761 SCV000077108 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-31 criteria provided, single submitter clinical testing This 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.
Ambry Genetics RCV000131394 SCV000186370 pathogenic Hereditary cancer-predisposing syndrome 2022-06-28 criteria provided, single submitter clinical testing The c.68_69delAG (p.E23Vfs*17) alteration, located in exon 2 (coding exon 1) of the BRCA1 gene, consists of a deletion of 2 nucleotides from position 68 to 69, causing a translational frameshift with a predicted alternate stop codon after 17 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this variant has an overall frequency of 0.021% (58/282442) total alleles studied. The highest observed frequency was 0.405% (42/10368) of Ashkenazi Jewish alleles. This alteration is one of three well-characterized Ashkenazi Jewish founder mutations, with an overall carrier frequency of nearly 1% in this population (Struewing, 1995; Hartge, 1999). Average female breast cancer and ovarian cancer risks (by age 70) associated with this specific mutation have been estimated at 64% (range: 34-80%) and 14% (range: 2-24%), respectively (Antoniou, 2005). Additionally, this germline mutation has been reported in individuals of Ashkenazi Jewish descent with personal and/or family history of pancreatic cancer (Lucas, 2013; Lucas, 2014). It has also been identified in multiple Spanish hereditary breast and ovarian cancer families (Gabaldó Barrios, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan RCV000019230 SCV000195875 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-11-03 criteria provided, single submitter clinical testing
Counsyl RCV000019230 SCV000220360 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-05-30 criteria provided, single submitter literature only
Eurofins Ntd Llc (ga) RCV000213650 SCV000227400 pathogenic not provided 2016-05-09 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000019230 SCV000266036 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000034761 SCV000271311 pathogenic Hereditary breast ovarian cancer syndrome 2020-09-01 criteria provided, single submitter clinical testing The 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.
GeneDx RCV000213650 SCV000278833 pathogenic not provided 2019-10-16 criteria provided, single submitter clinical testing Frameshift 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)
Color Diagnostics, LLC DBA Color Health RCV000131394 SCV000292122 pathogenic Hereditary cancer-predisposing syndrome 2023-03-13 criteria provided, single submitter clinical testing This 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213650 SCV000296272 pathogenic not provided 2023-03-09 criteria provided, single submitter clinical testing This 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019230 SCV000326390 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000034761 SCV000403078 pathogenic Hereditary breast ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000056295 SCV000540943 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000019230 SCV000564332 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-07-01 criteria provided, single submitter clinical testing
Genologica Medica RCV000019230 SCV000577914 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-01-01 criteria provided, single submitter clinical testing
Bioinformatics dept., Datar Cancer Genetics Limited, India RCV000019230 SCV000583605 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-07-14 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency RCV000034761 SCV000586860 pathogenic Hereditary breast ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine, Queen's University RCV000034761 SCV000588022 pathogenic Hereditary breast ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000019230 SCV000593688 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-12-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000213650 SCV000602669 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing The 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.
GeneKor MSA RCV000056295 SCV000693502 pathogenic Familial cancer of breast 2020-01-01 criteria provided, single submitter clinical testing This 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034761 SCV000699291 pathogenic Hereditary breast ovarian cancer syndrome 2017-08-10 criteria provided, single submitter clinical testing 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000019230 SCV000746289 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-12-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000213650 SCV000778781 pathogenic not provided 2022-12-15 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000131394 SCV000803154 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004554604 SCV000806982 pathogenic BRCA1-related disorder 2024-02-16 criteria provided, single submitter clinical testing The 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.
Mendelics RCV000034761 SCV000839317 pathogenic Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000019230 SCV000839891 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-05-25 criteria provided, single submitter clinical testing The 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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000735481 SCV000901065 pathogenic Breast and/or ovarian cancer 2022-03-04 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000019230 SCV000993552 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2019-01-22 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV000213650 SCV001250428 pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing BRCA1: PVS1, PM2, PS4:Moderate
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000213650 SCV001447639 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000213650 SCV001449768 pathogenic not provided 2014-06-05 criteria provided, single submitter clinical testing
Department of Pediatrics, Memorial Sloan Kettering Cancer Center RCV000056295 SCV001478110 pathogenic Familial cancer of breast 2020-12-15 criteria provided, single submitter research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000019230 SCV001499755 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-04-02 criteria provided, single submitter clinical testing
Molecular Endocrinology Laboratory, Christian Medical College RCV000019230 SCV002003976 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000213650 SCV002009407 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000213650 SCV002020211 pathogenic not provided 2023-08-24 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000034761 SCV002026049 pathogenic Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited RCV000019230 SCV002097608 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 criteria provided, single submitter clinical testing
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited RCV001836711 SCV002097613 pathogenic Invasive medullary breast carcinoma criteria provided, single submitter clinical testing
DASA RCV000019230 SCV002107151 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-03-05 criteria provided, single submitter clinical testing The 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000034761 SCV002525990 pathogenic Hereditary breast ovarian cancer syndrome 2022-03-22 criteria provided, single submitter clinical testing The 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.
Sema4, Sema4 RCV000131394 SCV002537890 pathogenic Hereditary cancer-predisposing syndrome 2021-10-07 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000213650 SCV002551076 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000019230 SCV002580991 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-06-17 criteria provided, single submitter clinical testing
New York Genome Center RCV000019230 SCV002764582 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-09 criteria provided, single submitter clinical testing The 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.
Fulgent Genetics, Fulgent Genetics RCV002496414 SCV002814217 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2022-05-04 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000019230 SCV004027730 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-03-27 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS3, PM5_STR
Neuberg Centre For Genomic Medicine, NCGM RCV000019230 SCV004100646 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000019230 SCV004212668 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-03-27 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000019230 SCV004823702 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-01-12 criteria provided, single submitter clinical testing This 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.
Genomic Medicine Lab, University of California San Francisco RCV000019230 SCV004847144 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-04-20 criteria provided, single submitter clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000019230 SCV005045898 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-05-27 criteria provided, single submitter clinical testing PVS1; PM5_PTC_Strong
OMIM RCV000019230 SCV000039518 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2008-10-01 no assertion criteria provided literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000034761 SCV000043189 pathogenic Hereditary breast ovarian cancer syndrome 2012-07-13 no assertion criteria provided research Converted during submission to Pathogenic.
OMIM RCV000019231 SCV000053475 risk factor Pancreatic cancer, susceptibility to, 4 2008-10-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019230 SCV000053880 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2013-11-14 no assertion criteria provided clinical testing
GeneReviews RCV000034761 SCV000086950 not provided Hereditary breast ovarian cancer syndrome no assertion provided literature only Founder variant in Ashkenazi Jews; accounts for 72% of pathogenic variants in this population
Breast Cancer Information Core (BIC) (BRCA1) RCV000019230 SCV000144169 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000019230 SCV000189887 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-07-24 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000034761 SCV000587006 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353942 SCV000591232 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000019230 SCV000733684 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735481 SCV000863618 pathogenic Breast and/or ovarian cancer 2016-06-22 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785197 SCV000923765 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
CZECANCA consortium RCV000735481 SCV001451786 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000034761 SCV001749327 not provided Hereditary breast ovarian cancer syndrome no assertion provided phenotyping only 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000213650 SCV001905815 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000213650 SCV001965465 pathogenic not provided no assertion criteria provided clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000034761 SCV002032172 pathogenic Hereditary breast ovarian cancer syndrome no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000213650 SCV002037545 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000019230 SCV002074718 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided phenotyping only 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.
BRCAlab, Lund University RCV000019230 SCV002589061 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-26 no assertion criteria provided clinical testing
CZECANCA consortium RCV003128128 SCV003804349 pathogenic Endometrial carcinoma 2023-02-21 no assertion criteria provided clinical testing
Cancer Genomics Lab, PINUM Cancer Hospital RCV003225925 SCV003914825 pathogenic Triple-negative breast cancer 2023-03-11 no assertion criteria provided clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000019230 SCV003927207 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-05-05 no assertion criteria provided clinical testing This 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.

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