Submissions for variant NM_007294.4(BRCA1):c.3400G>T (p.Glu1134Ter)

dbSNP: rs80357018

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031110	SCV000282306	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	RCV000203638	SCV000076191	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1134*) 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 cancer and ovarian cancer (PMID: 10644434, 11389159, 16284991, 25452441, 26833046, 27376475, 27836010). This variant is also known as 3519G>T. ClinVar contains an entry for this variant (Variation ID: 37529). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000048178	SCV000209892	pathogenic	not provided	2021-09-21	criteria provided, single submitter	clinical testing	Nonsense 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Bergthorsson 2001, Nedelcu 2002, Pal 2005, Couch 2015, Wei 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3519G>T; This variant is associated with the following publications: (PMID: 10644434, 29446198, 29752822, 31825140, 32380732, 31897316, 25452441, 23704984, 21702907, 16234499, 11748305, 11938448, 21233401, 16284991, 21913181, 19329713, 27221827, 11389159, 27836010, 27376475, 25525159, 29339979, 29805665, 31447099)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031110	SCV000325649	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031110	SCV000564367	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048178	SCV000600331	pathogenic	not provided	2021-04-30	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in affected individuals with breast and/or ovarian cancer (PMIDs: 17688236 (2007), 21233401 (2011), 25452441 (2015), 27376475 (2016), 27836010 (2016), 29339979 (2018), and 29752822 (2018)). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV000509963	SCV000608082	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	The p.E1134* pathogenic mutation (also known as c.3400G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3400. 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/families with hereditary breast and/or ovarian cancer (HBOC) (Wagner T et al. Genomics. 1999 Dec;62:369-76; Thomassen M et al. Acta Oncol. 2008;47:772-7; Rebbeck TR et al. Breast Cancer Res. 2016 11;18(1):112; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3; Wei H et al. Oncol Lett, 2018 Jun;15:9420-9428; Incorvaia L et al. Cancers (Basel), 2020 May;12:). Of note, this alteration is also designated as 3519G>T 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.
Color Diagnostics, LLC DBA Color Health	RCV000509963	SCV000688434	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-02	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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least 10 individuals and families affected with breast and ovarian cancer (PMID: 11389159, 11938448, 16284991, 18465347, 25452441, 27376475, 29339979, 29752822). This variant has been identified in 1/250824 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000203638	SCV000699029	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3400G>T (p.Glu1134X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 250824 control chromosomes. c.3400G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Nedelcu_2002, Thomassen_2008, Pal_2005). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000203638	SCV000966959	pathogenic	Hereditary breast ovarian cancer syndrome	2018-01-17	criteria provided, single submitter	clinical testing	The p.Glu1134X variant in BRCA1 has been reported in >20 individuals with BRCA1- associated cancers (Wagner 1999, Bergthorsson 2001, Nedelcu 2002, Pal 2005, Couc h 2015, Rebbeck 2016, Breast Cancer Information Core (BIC) database: https://res earch.nhgri.nih.gov/bic/) and was absent from large population studies. This non sense variant leads to a premature termination codon at position 1134, which is predicted to lead to a truncated or absent protein. Heterozygous loss of functio n of the BRCA1 gene is an established disease mechanism in individuals with here ditary breast and ovarian cancer (HBOC). In addition, this variant was classifie d as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (C linVar SCV000282306.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon presence in m ultiple affected individuals, absence in the general population and predicted im pact to the protein. ACMG/AMP Criteria applied: PVS1; PS4; PM2 (Richards 2015).
Revvity Omics, Revvity	RCV000048178	SCV002021654	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000203638	SCV002025957	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000203638	SCV002515196	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048178	SCV002551001	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031110	SCV004212724	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-14	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031110	SCV005045979	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000031110	SCV000053706	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-12-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031110	SCV000144751	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	RCV000203638	SCV000587308	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research