ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.66_67AG[1] (p.Glu23fs) (rs80357914)

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Total submissions: 44
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000213650 SCV000602669 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing The BRCA1 c.68_69delAG;p.Glu23fs variant (also known as 187delAG) has been described in the literature in multiple individuals affected with hereditary breast and ovarian cancer syndrome and is described in the ClinVar database (Variation ID: 17662, see link below). It is reported in the dbSNP variant database (rs386833395) and in the Genome Aggregation Database with an allele frequency of 0.01987 percent. This variant causes a frameshift and is predicted to result in a truncated or absent protein and is therefore considered to be pathogenic. References: Link to NCBI ClinVar for p.Glu23fs variant: http://www.ncbi.nlm.nih.gov/clinvar/variation/17662/
Ambry Genetics RCV000131394 SCV000186370 pathogenic Hereditary cancer-predisposing syndrome 2018-02-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Baylor Genetics RCV000056295 SCV000540943 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034761 SCV000043189 pathogenic Hereditary breast and ovarian cancer syndrome 2012-07-13 no assertion criteria provided research Converted during submission to Pathogenic.
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000019230 SCV000583605 pathogenic Breast-ovarian cancer, familial 1 2017-07-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019230 SCV000144169 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735481 SCV000901065 pathogenic Breast and/or ovarian cancer 2017-07-31 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000034761 SCV000586860 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Color RCV000131394 SCV000292122 pathogenic Hereditary cancer-predisposing syndrome 2015-01-12 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019230 SCV000326390 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000019230 SCV000220360 pathogenic Breast-ovarian cancer, familial 1 2014-05-30 criteria provided, single submitter literature only
Department of Medical Genetics,Oslo University Hospital RCV000019230 SCV000564332 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000034761 SCV000591232 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000034761 SCV000588022 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000019230 SCV000733684 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000213650 SCV000227400 pathogenic not provided 2016-05-09 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000019230 SCV000282348 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
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
GeneDx RCV000056295 SCV000108687 pathogenic Familial cancer of breast 2014-10-06 criteria provided, single submitter clinical testing This mutation is caused by the deletion of two nucleotides (AG) in BRCA1 exon 2, and is denoted c.68_69delAG at the cDNA level using current HGVS nomenclature, or Glu23ValfsX16 at the protein level. The mutation is also known as BRCA1 185delAG or 187delAG and is a founder mutation in the Ashkenazi Jewish population (Struewing 1995). The deletion causes a frameshift, which changes a Glutamic acid to a Valine at codon 23 and creates a premature stop codon at position 16 of the new reading frame. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA1-related cancer risks for women who have not been diagnosed with cancer have been estimated to be 57% - 84% lifetime risk for breast cancer and 24% - 54% lifetime risk for ovarian cancer (Antoniou 2003, Chen 2007, Ford 1998). BRCA1 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Pennington 2013). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA1 mutation include approximately 3% risk for pancreatic cancer (The Breast Cancer Linkage Consortium 1999), a 20% risk for prostate cancer (Thompson 2002), and 4% risk for male breast cancer (Liede 2004). The variant is found in BR-OV-HEREDIC,BRCA1-BRCA2,BRCA-AJ,HIRISK-BR-HEREDIC,HEREDICANCER panel(s).
GeneDx RCV000213650 SCV000278833 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted BRCA1 c.68_69delAG at the cDNA level and p.Glu23ValfsX17 (E23VfsX17) at the protein level. The variant is also known as BRCA1 185delAG or 187delAG using alternate nomenclature and is one of three main pathogenic founder variants in the Ashkenazi Jewish population (Struewing 1995). The normal sequence, with the bases that are deleted in brackets, is TTAG[delAG]TGTC. The deletion causes a frameshift, which changes a Glutamic Acid to a Valine at codon 23, and creates a premature stop codon at position 17 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
GeneKor MSA RCV000056295 SCV000693502 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
GeneReviews RCV000056295 SCV000086950 pathologic Familial cancer of breast 2013-09-26 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000019230 SCV000593688 pathogenic Breast-ovarian cancer, familial 1 2016-12-02 criteria provided, single submitter clinical testing
Genologica Medica RCV000019230 SCV000577914 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000019230 SCV000746289 pathogenic Breast-ovarian cancer, familial 1 2017-12-03 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785197 SCV000923765 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000019230 SCV000993552 pathogenic Breast-ovarian cancer, familial 1 2019-01-22 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000019230 SCV000839891 pathogenic Breast-ovarian cancer, familial 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
Illumina Clinical Services Laboratory,Illumina RCV000034761 SCV000403078 pathogenic Hereditary breast and 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.
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
Integrated Genetics/Laboratory Corporation of America RCV000034761 SCV000699291 pathogenic Hereditary breast and 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.
Invitae RCV000034761 SCV000077108 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-04 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000034761 SCV000271311 pathogenic Hereditary breast and ovarian cancer syndrome 2016-01-19 criteria provided, single submitter clinical testing The p.Glu23ValfsX17 variant in BRCA1 has been reported in numerous individuals w ith hereditary breast and ovarian cancer (HBOC) and is a known pathogenic Ashken azi Jewish founder variant (Struewing 1997, Abeliovich 2013). It has also been i dentified in 38/10150 Ashkenazi Jewish and 11/126308 European chromosomes by gno mAD (http://gnomad.broadinstitute.org). Please note that this frequency is low e nough to be consistent with the frequency of HBOC in the general population. Thi s frameshift variant is predicted to alter the protein?s amino acid sequence beg inning at position 23 and lead to a premature termination codon 17 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Additionally, this variant was classified a s Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Clin Var SCV000282348.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted im pact to the protein and presence in multiple affected individuals. ACMG/AMP Crit eria applied: PVS1, PS4_strong.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000213650 SCV000778781 pathogenic not provided 2016-11-29 no assertion criteria provided clinical testing
Mendelics RCV000034761 SCV000839317 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000019230 SCV000195875 pathogenic Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
OMIM RCV000019230 SCV000039518 pathogenic Breast-ovarian cancer, familial 1 2008-10-01 no assertion criteria provided literature only
OMIM RCV000019231 SCV000053475 risk factor Pancreatic cancer 4 2008-10-01 no assertion criteria provided literature only
Pathway Genomics RCV000019230 SCV000189887 pathogenic Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided clinical testing
PreventionGenetics RCV000213650 SCV000806982 pathogenic not provided 2016-07-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213650 SCV000296272 pathogenic not provided 2015-02-12 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000034761 SCV000587006 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000019230 SCV000053880 pathogenic Breast-ovarian cancer, familial 1 2013-11-14 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000019230 SCV000266036 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing

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