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

dbSNP: rs80357914

Total submissions: 81

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).
Labcorp Genetics (formerly Invitae), Labcorp	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
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	2024-08-01	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	2023-06-08	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4
Neuberg Centre For Genomic Medicine, NCGM	RCV000019230	SCV004100646	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-20	criteria provided, single submitter	clinical testing	The frameshift c.68_69del (p.Glu23ValfsTer17) variant in the BRCA1 gene has been reported in a heterozygous state in individuals affected with Hereditary Breast and Ovarian Cancer (Petrucelli N et al. 2022; Rajagopal T et al., 2022). Functional assays showed this variant was deleterious (Bouwman P et al. 2013). The p.Glu23ValfsTer17 variant has an allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Glutamic Acid 23, changes this amino acid to Valine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Glu23ValfsTer17. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. 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
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000213650	SCV005198273	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056295	SCV005368055	pathogenic	Familial cancer of breast	2024-04-02	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4_MOD,PM5_STR
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
PreventionGenetics, part of Exact Sciences	RCV004554604	SCV000806982	pathogenic	BRCA1-related disorder	2024-02-16	no assertion criteria provided	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.
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	Ovarian neoplasm	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.
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000019230	SCV005061273	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control