Submissions for variant NM_007294.4(BRCA1):c.2019del (p.Glu673fs)

dbSNP: rs80357626

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077504	SCV000282271	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.
Invitae	RCV000047685	SCV000075698	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54438). This variant is also known as 2137delA and 2138delA. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 12112655, 14871810, 16683254, 23635950, 24307375). It is commonly reported in individuals of Dutch ancestry (PMID: 16683254, 24307375). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu673Aspfs*28) 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).
Ambry Genetics	RCV000167502	SCV000218360	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-09	criteria provided, single submitter	clinical testing	The c.2019delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2019, causing a translational frameshift with a predicted alternate stop codon (p.E673Dfs*28). This deletion has been reported in numerous high risk breast and/or ovarian cancer families (Yazici H, Hum. Mutat. 2002 Jul; 20(1):28-34, van der Hout AH, Hum. Mutat. 2006 Jul; 27(7):654-66, Dobrii J, J. Hum. Genet. 2013 Aug; 58(8):501-7; Jacobi CE et al. Genet. Med. 2007 Mar;9(3):173-9; Hermsen BB et al. Int. J. Cancer 2006 Sep;119(6):1412-8; Dacheva D et al. Mol Diagn Ther 2015 Apr;19(2):119-30). Of note, this alteration is also designated as 2137delA and 2138delA in published literature. 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077504	SCV000325214	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077504	SCV000564341	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000479187	SCV000568424	pathogenic	not provided	2017-09-05	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.2019delA at the cDNA level and p.Glu673AspfsX28 (E673DfsX28) at the protein level. Using alternate nomenclature, this variant has previously been published as BRCA1 2138delA and 2137delA. The normal sequence, with the base that is deleted in braces, is AAGA[A]CCTG. The deletion causes a frameshift which changes a Glutamic Acid to an Aspartic Acid at codon 673, and creates a premature stop codon at position 28 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2019delA has been reported in multiple individuals with personal and/or family histories of breast and ovarian cancer and is a common pathogenic variant in the Dutch population (Yazici 2002, Szabo 2004, Hermsen 2006, Jacobi 2007, Dobricic 2013, Brohet 2014). We consider this variant to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000167502	SCV000688362	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047685	SCV000698907	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-13	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2019delA (p.Glu673Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If the variant escapes NMD, it is predicted to truncate BCRT domain (InterPro, UniProt). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1135X, p.Gln1200X, p.Glu1250X, etc.). This variant is absent from 121362 control chromosomes from ExAC. This variant has been reported in multiple affected HBOC patients/families in literature and clinical databases. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077504	SCV000744667	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077504	SCV000109304	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2008-03-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077504	SCV000144278	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-02	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047685	SCV000587179	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077504	SCV000733650	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000479187	SCV001906152	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000479187	SCV002037403	pathogenic	not provided		no assertion criteria provided	clinical testing
Medical Genetics, Medical University Pleven	RCV000077504	SCV004100889	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	research
BRCAlab, Lund University	RCV000077504	SCV004244105	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing