Submissions for variant NM_007294.4(BRCA1):c.2641G>T (p.Glu881Ter)

dbSNP: rs397508988

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000225552	SCV000282284	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000225552	SCV000325414	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478682	SCV000566938	pathogenic	not provided	2017-01-04	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.2641G>T at the cDNA level and p.Glu881Ter (E881X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 Glu881Ter has been observed in association with hereditary breast and/or ovarian cancer, and is reported to be an Afrikaner pathogenic founder variant (Reeves 2004, van der Merwe 2012, Plaskocinska 2016). We therefore consider this variant to be pathogenic.
Ambry Genetics	RCV000563817	SCV000661051	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.E881* pathogenic mutation (also known as c.2641G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2641. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been reported in multiple individuals from the South African Afrikaner population with significant personal and family histories of breast and/or ovarian cancer, and is regarded as a founder mutation in this population (van der Merwe NC et al. Clin. Genet. 2012 Feb; 81(2):179-84; Schoeman M et al. S. Afr. Med. J. 2013 Aug; 103(8):529-33; Reeves MD et al. Int. J. Cancer 2004 Jul; 110(5):677-82; Loubser F et al. Clin. Genet. 2012 Dec; 82(6):599-600; Seymour HJ et al. S. Afr. Med. J. 2016 Mar; 106(3):264-7). Of note, this alteration is also designated as 2760G>T in the 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.
Color Diagnostics, LLC DBA Color Health	RCV000563817	SCV000688394	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is reported as a common cause of hereditary breast and ovarian cancer in individuals of Afrikaner ancestry (PMID: 15146556, 23885733, 26915939, 28918466). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496821	SCV001590812	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu881*) 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: 15146556, 23885733, 26915939). It is commonly reported in individuals of Afrikaner ancestry (PMID: 15146556, 23885733, 26915939). This variant is also known as 2760G>T. ClinVar contains an entry for this variant (Variation ID: 54625). For these reasons, this variant has been classified as Pathogenic.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000496821	SCV002504999	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000225552	SCV004211748	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-07-22	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000225552	SCV005061264	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The stop-gained variant c.2641G>T (p.Glu881Ter) in the BRCA1 gene has been reported previously in heterozygous state in multiple patients affected with Breast and Ovarian Cancer (Van der Merwe et al., 2022; Seymour et al., 2016). The c.2641G>T variant is novel (not in any individuals) in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). 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.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496821	SCV000587242	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research