Submissions for variant NM_007294.4(BRCA1):c.5251C>T (p.Arg1751Ter)

gnomAD frequency: 0.00003  dbSNP: rs80357123

Total submissions: 45

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077611	SCV000282340	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	RCV000048882	SCV000076895	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1751*) 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 present in population databases (rs80357123, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast and ovarian cancer (PMID: 9361038, 21232165, 21324516, 24010542, 25428789, 27433846). This variant is also known as 5370C>T. ClinVar contains an entry for this variant (Variation ID: 55480). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074600	SCV000108685	pathogenic	not provided	2022-04-28	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 (Vehmanen 1997, Sarantaus 2001, Stavropoulou 2013, Churpek 2015, Szwiec 2015, Alemar 2016, Pritchard 2016, Brovkina 2018); Published functional studies demonstrate a damaging effect: unable to support viability in a haploid cell line (Findlay 2018); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5370C>T; This variant is associated with the following publications: (PMID: 24528374, 26852015, 27393621, 27514839, 18783588, 17148771, 23199084, 29310832, 21324516, 25525159, 9361038, 26287763, 23536787, 26843898, 26779294, 27167707, 27082205, 27425403, 27756336, 27533253, 27836010, 27433846, 20614009, 24010542, 21232165, 18821011, 16528604, 28324225, 28985766, 23469205, 29339979, 29752822, 29907814, 28993434, 28724667, 22652532, 22434525, 12142080, 11436123, 18159056, 25428789, 17453335, 30209399, 30333958, 31174498, 30702160, 29161300, 30078507, 29446198, 28176296, 30199306, 32295079, 33084842, 30787465, 34011307, 31447099, 32341426, 31825140)
Ambry Genetics	RCV000162884	SCV000213371	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The p.R1751* pathogenic mutation (also known as c.5251C>T), located in coding exon 18 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5251. This changes the amino acid from an arginine to a stop codon within coding exon 18. This mutation has been reported in multiple breast and/or ovarian cancer families from various ethnicities to date and has been described as a European founder mutation (Vehmanen P et al. Hum. Mol. Genet. 1997 Dec;6:2309-15; Sinilnikova OM et al. Fam. Cancer. 2006;5:15-20; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Janaviius R. EPMA J. 2010 Sep;1:397-412; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Szwiec M et al. Clin. Genet. 2015 Mar;87:288-92; Zhang J et al. Breast Cancer Res. Treat. 2016 Aug;158:455-62; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). This mutation has also been reported in gastric cancer patients (awniczak M et al. Hered Cancer Clin Pract. 2016 Jan;14:3), as well as in a study of men with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this mutation is also designated as 5370C>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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074600	SCV000296322	pathogenic	not provided	2019-04-19	criteria provided, single submitter	clinical testing	This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in multiple individuals and families with breast and/or ovarian cancer or prostate cancer in the published literature (PMID: 29752822 (2018), 27433846 (2016), 25428789 (2015), 21324516 (2011), 9361038 (1997)). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000048882	SCV000296780	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This is a single base substitution, replacing Arginine with a termination codon. It is expected to result in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic. This particular variant is also known as 5370C>T and it has been described in the literature in multiple individuals with breast and ovarian cancer (PMID 21324516, 9361038) and in an individual with prostate cancer (PMID: 27433846). The mutation database ClinVar contains entries for this variant (Variation ID: 55480).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077611	SCV000326226	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077611	SCV000488332	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414226	SCV000492472	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Department of Medical Genetics, Oslo University Hospital	RCV000077611	SCV000564307	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048882	SCV000605749	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-30	criteria provided, single submitter	clinical testing	The p.Arg1751X variant in BRCA1 has been identified in >50 individuals with BRCA1-associated cancers (Konstantopoulou 2014 PMID: 17453335, Stegal 2011 PMID:21232165, Stavropoulou 2013 PMID: 23536787, Breast Cancer Information Core (BIC) database). It has also been identified in 0.005% (1/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA Expert Panel (Variation ID 55480). This nonsense variant leads to a premature termination codon at position 1751, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2.
Color Diagnostics, LLC DBA Color Health	RCV000162884	SCV000683276	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 19 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in over 20 individuals affected with breast and ovarian cancer (PMID: 12142080, 17453335, 18159056, 21324516, 23469205, 23536787, 24010542, 25428789, 26287763, 27393621, 30287823, 32856862, 33471991, 35205313; Leiden Open Variation Database DB-ID BRCA1_000435) and an individual affected with prostate cancer (PMID: 27433846). This variant has been identified in 94 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 4/282892 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	RCV000048882	SCV000699227	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-18	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5251C>T (p.Arg1751X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.5266dupC (p.Glh1756fsX74), c.5289delG (p.Leu1764X), and c.5335delC (p.Gln1779fsX14)). The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple databases/clinical diagnostic laboratories cite the variant as "Pathogenic/Causal." Therefore, the variant of interest has been classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077611	SCV000743375	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077611	SCV000744590	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077611	SCV000839894	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-25	criteria provided, single submitter	clinical testing	The c.5251C>T (p.Arg1751*) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 9361038, 21324516, referred as c.5370C>T] and prostate cancer [PMID 27433846]. This variant creates a premature stop codon at amino acid position 1751 of the BRCA1 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant thus classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763399	SCV000894125	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000074600	SCV001447498	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000077611	SCV001499706	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000074600	SCV001747801	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000077611	SCV002003982	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162884	SCV002537828	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000077611	SCV002581426	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-02-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000077611	SCV002764912	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-12-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000074600	SCV003809890	pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000074600	SCV004026749	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000077611	SCV004027825	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-16	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4,PM2_SUP
Human Genetics Bochum, Ruhr University Bochum	RCV000077611	SCV004042801	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-29	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM2_SUP
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000048882	SCV004183376	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated
Baylor Genetics	RCV000077611	SCV004215033	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000074600	SCV004224783	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	PP5, PM2, PS3_supporting, PVS1
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000077611	SCV004806683	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-26	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000074600	SCV005199698	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077611	SCV000109414	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-09-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077611	SCV000145411	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000077611	SCV000212009	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048882	SCV000587482	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074600	SCV000591597	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Arg1751X variant has been previously reported in the literature in at least 14 of 6217 individuals with hereditary breast and ovarian cancer and was consistent with a pathogenic role for this variant (Vehmanen 1997, Zhang 2011, Ladopoulou 2002, Schulz 2012, Papi 2009, Risch 2006, Krajc 2008, Sarantaus 2001, Fostira 2012). In a limited number of control chromosomes (186) the variant was not identified in these studies. This variant was also listed in the UMD (13x), LOVD, COSMIC and BIC (33x as clinically important) databases. The p.Arg1751X variant results in a premature stop codon at position 1751, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077611	SCV000733592	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786961	SCV000925866	pathogenic	Familial cancer of breast	2018-10-17	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077611	SCV001242472	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
CZECANCA consortium	RCV001270975	SCV001451780	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000074600	SCV001906148	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074600	SCV001952183	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077611	SCV002588830	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing