Submissions for variant NM_007294.4(BRCA1):c.5080G>T (p.Glu1694Ter)

dbSNP: rs80356896

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)	RCV000077593	SCV000300196	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048780	SCV000076793	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1694*) in the BRCA1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs80356896, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 9497265). This variant is also known as 5199G>T. ClinVar contains an entry for this variant (Variation ID: 55387). Studies have shown that this premature translational stop signal results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 11137998). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Asp1692_Phe1717del) have been determined to be pathogenic (PMID: 9497265). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000255531	SCV000321439	pathogenic	not provided	2020-07-29	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in the in-frame skipping of exon 17, also denoted exon 18, resulting in disruption of the BRCT domain (Mazoyer 1998, Liu 2001, Perrin-Vidoz 2002); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Shattuck-Eidens 1997, Liu 2001, Schoumacher 2001, Meindl 2002, Kim 2012); Published functional studies demonstrate a damaging effect: classified as non-functional based a saturation genome editing assay measuring cell viability (Findlay 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9497265, 11137998, 12393792, 27281844, 31924417, 32098980, 30207098, 32019277, 29673794, 25863477, 27026398, 29446198, 28111427, 30209399, 29020732, 25525159, 18391021, 12145750, 22798144, 16825284, 16267036, 12955719, 11802209, 11400546, 9333265, 29346284)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077593	SCV000326151	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580802	SCV000683251	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-12	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 17 of the BRCA1 gene, creating a premature translation stop signal. This sequence change is expected to result in an absent or non-functional protein product. In addition, RNA studies have shown that this variant disrupts an exonic splice enhancer motif and causes aberrant splicing, resulting in an in-frame skipping of exon 17 (exon 18 based on BIC nomenclature; p.Asp1692_Phe1717del) (PMID: 9497265, 11137998). The mutant protein lacking 26 amino acids from the conserved BRCT domain is expected to be dysfunctional. This variant has been reported in over ten individuals affected with breast cancer (PMID: 9497265, 10464631, 11802209, 22798144, 25863477). This variant has been identified in 1/251136 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077593	SCV000744601	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580802	SCV001185403	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-03	criteria provided, single submitter	clinical testing	The c.5080G>T (p.E1694*) alteration, located in exon 17 (coding exon 16) of the BRCA1 gene, consists of a G to T substitution at nucleotide position 5080. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 1694. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This pathogenic mutation has been reported in numerous individuals with personal and/or family histories consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Shattuck-Eidens, 1997; Kang, 2015; Eoh, 2017; Park 2017; Kwon, 2019; Kim, 2018; Rebbeck, 2018). This pathogenic mutation has also been reported in a double heterozygote state in conjunction with a BRCA2 mutation (Loader, 1998). Functional analyses have shown this pathogenic mutation results in disruption of an ESE motif leading to skipping of coding exon 17 of the BRCA1 gene and that it has a deleterious impact on cell survival in a high throughput genome editing assay (Ambry internal data; Mazoyer, 1998; Liu, 2001; Goina, 2008; Findlay, 2018). Of note, this alteration is also designated as 5199G>T in published literature. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255531	SCV001247344	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255531	SCV002020189	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077593	SCV004216840	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255531	SCV004219439	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251136 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 28111427 (2017), 29020732 (2018), 29446198 (2018), 30207098 (2018), 31825140 (2019), 32019277 (2020), 32455662 (2020), and 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). The variant is found to impact splicing by skipping exon 18 and creating an in-frame deletion within the highly conserved BRCT1 domain (PMIDs: 9497265 (1998) and 18391021 (2008)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048780	SCV005421987	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5080G>T (p.Glu1694X) 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. Publications report experimental evidence that this variant affects mRNA splicing and results in the in-frame skipping of exon 18 (also referred to as exon 17 in the literature; e.g. Mazoyer_1998, Liu_2001), an exon in which multiple variants have been classified as pathogenic by our laboratory and others in ClinVar, supporting the critical relevance of this region to BRCA1 function. The variant allele was found at a frequency of 4e-06 in 251136 control chromosomes. c.5080G>T has been reported in the literature in multiple individuals/families affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Mazoyer_1998, Loader_1998a, Loader_1998b, Judkins_2005, Kim_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11137998, 16267036, 10464609, 22798144, 9333265, 10464601, 25863477, 9497265). ClinVar contains an entry for this variant (Variation ID: 55387). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077593	SCV000109396	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2006-11-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077593	SCV000145303	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	RCV000048780	SCV000587458	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077593	SCV000733600	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077593	SCV001242087	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255531	SCV001951863	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554685	SCV004108975	pathogenic	BRCA1-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The BRCA1 c.5080G>T variant is predicted to result in premature protein termination (p.Glu1694*). This variant has been reported in multiple individuals with breast and/or ovarian cancer (Shattuck-Eidens et al. 1997. PubMed ID: 9333265; Park et al. 2017. PubMed ID: 28111427; Table S2, Eoh et al. 2017. PubMed ID: 29020732; reported as c.5199G>T in Mazoyer et al. 1998. PubMed ID: 9497265). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and it is classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55387/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.