Submissions for variant NM_007294.4(BRCA1):c.2263G>T (p.Glu755Ter)

dbSNP: rs41286296

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111810	SCV000299734	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111810	SCV000325309	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092621	SCV001249206	pathogenic	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001092621	SCV001447292	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496395	SCV001586755	pathogenic	Hereditary breast ovarian cancer syndrome	2019-09-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 9150174, 29446198). ClinVar contains an entry for this variant (Variation ID: 54516). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu755*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000111810	SCV002505521	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-07-13	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001092621	SCV004026326	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	PS4_MOD, PVS1, PM2_SUP
Baylor Genetics	RCV000111810	SCV005058235	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004601099	SCV005100923	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	The p.E755* pathogenic mutation (also known as c.2263G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2263. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This variant was reported in multiple individuals with features consistent with BRCA1-related hereditary breast and ovarian cancer syndrome (Ramus SJ et al. Am J Hum Genet, 1997 May;60:1242-6; Foretova L et al. Hum Mutat, 2004 Apr;23:397-8; Machackova E et al. BMC Cancer, 2008 May;8:140). Of note, this variant is also designated as 2382G>T in the 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001092621	SCV005199738	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111810	SCV000144359	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496395	SCV000587203	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
CZECANCA consortium	RCV001270970	SCV001451775	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356914	SCV001552204	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu755* variant was identified in 7 of 1280 proband chromosomes (frequency: 0.005) from individuals or families with breast or ovarian cancer (Foretova 2004, Machackova 2008, Pohlreich 2005). The variant was also identified in dbSNP (ID: rs41286296) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as pathogenic by ENIGMA, CIMBA, COGR and BIC), and in LOVD 3.0 (6x as pathogenic). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2263G>T variant leads to a premature stop codon at position 755 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in BRCA1 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
CZECANCA consortium	RCV001391198	SCV001593141	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	clinical testing