Submissions for variant NM_007294.4(BRCA1):c.66dup (p.Glu23fs)

dbSNP: rs80357783

Total submissions: 41

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031272	SCV000282347	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049087	SCV000077100	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu23Argfs*18) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8595420, 12181777, 16998791, 20189727, 24916970). This variant is also known as 185insA. ClinVar contains an entry for this variant (Variation ID: 37691). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000163427	SCV000213973	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-30	criteria provided, single submitter	clinical testing	The c.66dupA pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of one nucleotide at position 66, causing a translational frameshift with a predicted alternate stop codon (p.E23Rfs*18). This mutation has been described in numerous breast and ovarian cancer patients and families (Couch FJ and Weber BL. Hum. Mutat. 1996;8:8-18; Rashid MU et al. Int. J. Cancer. 2006 Dec;119:2832–39; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bujassoum SM et al. J. Cancer Sci. Ther. 2017;9(2):358-64). Of note, this alteration is also designated as 185insA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000478017	SCV000227401	pathogenic	not provided	2014-09-05	criteria provided, single submitter	clinical testing
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240681	SCV000265852	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478017	SCV000296291	pathogenic	not provided	2023-07-11	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35918668 (2022), 35220195 (2022), 34290354 (2021), 32733560 (2020), 29470806 (2018), 29176636 (2018)) and endometrial cancer (PMID: 31492746 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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	RCV000031272	SCV000326376	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031272	SCV000488962	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-07-26	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031272	SCV000564309	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000478017	SCV000564708	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history consistent with pathogenic variants in this gene (Kroiss et al., 2005; Rashid et al., 2006; Thirthagiri et al., 2008; Noel et al., 2010; Ginsburg et al., 2011; Peixoto et al., 2014; Heramb et al., 2018); 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; Not observed in large population cohorts (gnomAD); Also known as 185dupA or 185insA; This variant is associated with the following publications: (PMID: 8595420, 27157322, 10952777, 29339979, 29752822, 16287141, 30078507, 31492746, 20189727, 26187060, 22798144, 25103822, 23374397, 24916970, 20950396, 18627636, 12181777, 28179634, 27257965, 16998791, 29907814, 29116469, 29433453, 28993434, 8807330, 30702160, 27553291, 29470806, 28176296, 31528241, 32733560, 32341426, 29176636, 31742824, 31825140, 30787465, 11597388, 35220195, 34290354, 32211327, 15026808, 35264596, 35377489, 31892343)
GeneKor MSA	RCV000478017	SCV000693501	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change inserts one nucleotide in exon 2 of BRCA1 mRNA (c.66dupA), causing a frameshift at codon 23 and the creation of a premature translation stop signal 18 amino acid residues later. This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant is also known as 185insA in the literature and it has been reported in the literature in individuals and families with breast and/or ovarian cancer (PMID: 8595420, 20189727, 24916970, 16998791). The mutation database ClinVar contains entries for this variant (Variation ID: 37691).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049087	SCV000699283	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.66dupA (p.Glu23Asnfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln60X, p.Tyr101X, p.Glu143X, etc.). This variant is absent in 120930 control chromosomes from ExAC. The variant is a recurrent pathogenic variant found in several HBOC patients/families and in individuals undergoing BRCA1/2 testing. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Mendelics	RCV000049087	SCV000839318	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163427	SCV000911363	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 Individuals affected with breast and ovarian cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected individual (PMID: 8595420, 11606101, 12181777, 18627636, 20189727, 20950396, 27257965, 28993434, 29152070, 29470806, 33471991, 35918668; Leiden Open Variation Database DB-ID BRCA1_001098), and in suspected hereditary breast and ovarian cancer families (PMID: 10952777, 16683254, 16998791, 21559243, 24916970, 25863477, 29176636, 29339979, 29907814). This variant also has been reported in an individual affected with melanoma (PMID: 29433453). This variant has not been identified 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.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000778174	SCV000914333	pathogenic	Familial cancer of breast	2019-01-30	criteria provided, single submitter	research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000031272	SCV001499756	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000031272	SCV002003984	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000049087	SCV002026050	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163427	SCV002537883	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000478017	SCV003809723	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031272	SCV004027618	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu23Argfs*18) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8595420, 12181777, 16998791, 20189727, 24916970). This variant is also known as 185insA. ClinVar contains an entry for this variant (Variation ID: 37691) classified as pathogenic , reviewed by expert panel. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000031272	SCV004215028	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-08	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000478017	SCV005199764	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802995	SCV005424226	pathogenic	BRCA1-related cancer predisposition	2024-09-03	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 Individuals affected with breast and ovarian cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected individual (PMID: 8595420, 11606101, 12181777, 18627636, 20189727, 20950396, 27257965, 28993434, 29152070, 29470806, 33471991, 35918668; Leiden Open Variation Database DB-ID BRCA1_001098), and in suspected hereditary breast and ovarian cancer families (PMID: 10952777, 16683254, 16998791, 21559243, 24916970, 25863477, 29176636, 29339979, 29907814). This variant also has been reported in an individual affected with melanoma (PMID: 29433453). This variant has not been identified 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.
Fulgent Genetics, Fulgent Genetics	RCV005007902	SCV005640307	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-04-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000478017	SCV005872206	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031272	SCV000053877	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031272	SCV000144170	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000049087	SCV000587005	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785198	SCV000923766	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000778174	SCV000925806	pathogenic	Familial cancer of breast	2018-11-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000478017	SCV001552235	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000478017	SCV001741091	pathogenic	not provided		no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554246	SCV001774819	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000478017	SCV001797997	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000478017	SCV001906189	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000478017	SCV001931017	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000478017	SCV001972604	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000778174	SCV002520918	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000031272	SCV004244205	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758615	SCV005363303	pathogenic	BRCA1-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The BRCA1 c.66dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu23Argfs*18). This variant is alternatively referred to as 185insA. This variant has been reported in many individuals and families with breast and/or ovarian cancer (Matsushima et al. 1995. PubMed ID: 8595420; Couch et al. 1996. PubMed ID: 8807330; Liede et al. 2002. PubMed ID: 12181777; Rashid et al. 2006. PubMed ID: 16998791; Noël et al. 2010. PubMed ID: 20189727; PubMed ID: 24916970; Arai et al. 2017. PubMed ID: 29176636; Heramb et al. 2018. PubMed ID: 29339979; Li et al. 2018. PubMed ID: 29752822; Bhaskaran et al. 2019. PubMed ID: 30702160). It has also been reported in a male individual with melanoma (Ibrahim et al. 2018. PubMed ID: 29433453). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37691/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.