rs80357914
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM5_StrongPS3PVS1
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003783/MONDO:0011450/092
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.57
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
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Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.68_69del | p.Glu23ValfsTer17 | frameshift_variant | 2/23 | ENST00000357654.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.68_69del | p.Glu23ValfsTer17 | frameshift_variant | 2/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000227 AC: 57AN: 251050Hom.: 0 AF XY: 0.000251 AC XY: 34AN XY: 135676
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:74Other:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:30Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 25, 2017 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 05, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 02, 2016 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jan 22, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Bioinformatics dept., Datar Cancer Genetics Limited, India | Jul 14, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, 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 submitter | clinical testing | GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Endocrinology Laboratory, Christian Medical College | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Apr 20, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg 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, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 12, 2024 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2008 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Aug 09, 2022 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 27, 2024 | Criteria applied: PVS1,PS3, PM5_STR - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 14, 2013 | - - |
| Pathogenic, criteria provided, single submitter | literature only | Counsyl | May 30, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | 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. - |
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 09, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 15, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2019 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 27, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 05, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | BRCA1: PVS1, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 09, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:12Other:2
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | 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. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect - 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 submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 01, 2020 | 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. - |
| Pathogenic, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | 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. - |
| not provided, no classification provided | literature only | GeneReviews | - | Founder variant in Ashkenazi Jews; accounts for 72% of pathogenic variants in this population - |
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 22, 2022 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 13, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 28, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 23, 2018 | - - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 07, 2021 | - - |
Breast and/or ovarian cancer Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jun 22, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 04, 2022 | - - |
Familial cancer of breast Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | 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). - |
| Pathogenic, criteria provided, single submitter | research | Department of Pediatrics, Memorial Sloan Kettering Cancer Center | Dec 15, 2020 | - - |
Invasive medullary breast carcinoma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited | - | - - |
Triple-negative breast cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Cancer Genomics Lab, PINUM Cancer Hospital | Mar 11, 2023 | - - |
Neoplasm of ovary Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
BRCA1-related cancer predisposition Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Jun 11, 2024 | 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). - |
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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 04, 2022 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department 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. - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2024 | 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. - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Pancreatic cancer, susceptibility to, 4 Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Oct 01, 2008 | - - |
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