Submissions for variant NM_007294.4(BRCA1):c.4689C>G (p.Tyr1563Ter)

gnomAD frequency: 0.00001  dbSNP: rs80357433

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031188	SCV000282332	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.
Invitae	RCV000048631	SCV000076644	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1563*) 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 (rs80357433, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 8554067, 20727672, 23110154, 25066507, 27167707). It has also been observed to segregate with disease in related individuals. This variant is also known as 4808C>G. ClinVar contains an entry for this variant (Variation ID: 37607). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131835	SCV000186890	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The p.Y1563* pathogenic mutation (also known as c.4689C>G), located in coding exon 14 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4689. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Iyevleva AG et al. Cancer Lett. 2010 Dec;298:258-63; Schneegans S et al. Fam. Cancer. 2012 Jun;11:181-8; Lecarpentier J et al. Breast Cancer Res. 2012 Jul;14:R99; Pern F et al. PLoS One. 2012;7:e47993; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620), and a history weighing algorithm classified it as pathogenic (Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). One study demonstrated that this mutation triggers nonsense mediated decay (NMD) and results in less than half the amount of BRCA1 mRNA compared to wild-type (Perrin-Vidoz L et al. Hum. Mol. Genet. 2002 Nov;11:2805-14). Of note, this alteration is also designated as 4808C>G 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.
GeneDx	RCV000159994	SCV000210185	pathogenic	not provided	2022-11-30	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 (Serova 1996, Shih 2002, Turkovic 2010, Schneegans 2012, Wong-Brown 2015, Nguyen-Dumont 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 4808C>G; This variant is associated with the following publications: (PMID: 27167707, 30128899, 29422015, 30551077, 34657373, 29922827, 30040829, 28888541, 11844822, 8554067, 22160602, 23110154, 25556971, 24830819, 25682074, 26843898, 25948282, 25085752, 29339979, 28324225, 29907814, 29446198, 30487145, 30216591, 30322717, 20807450, 32072338, 30787465, 30612635, 29625052, 31447099, 35596902, 36367610, 36171877)
Eurofins Ntd Llc (ga)	RCV000159994	SCV000226313	pathogenic	not provided	2015-05-14	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031188	SCV000267714	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031188	SCV000326033	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031188	SCV000488572	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000464295	SCV000540932	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031188	SCV000564327	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000031188	SCV000593676	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131835	SCV000683206	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 15 of the BRCA1 gene, creating a premature translation stop signal. RNA analyses have shown that this variant leads to an absence of RNA transcript and protein product (PMID: 8554067, 12393792). This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 8554067, 11844822, 15951958, 20727672, 20807450, 22160602, 22711857, 22762150, 23110154, 25066507, 25452441, 27167707, 29339979, 33471991). This variant has been identified in 1/250704 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.
GeneKor MSA	RCV000159994	SCV000693540	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 1563 (p.Tyr1563*). It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular truncation has been reported in the literature in individuals affected with hereditary breast and ovarian cancer (PMID: 8554067, 23110154, 25066507, 20727672, 27167707). This sequence change is also known as 4808C>G in the literature. This particular variant has been described in the mutation database ClinVar (Variation ID: 37607) as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048631	SCV000699164	pathogenic	Hereditary breast ovarian cancer syndrome	2020-07-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4689C>G (p.Tyr1563X) 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 250704 control chromosomes (gnomAD). c.4689C>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Alsop_2012, Bergman_2005, Couch_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 21 ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031188	SCV000743389	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	RCV000031188	SCV000744610	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003389674	SCV000806958	pathogenic	BRCA1-related condition	2023-10-03	criteria provided, single submitter	clinical testing	The BRCA1 c.4689C>G variant is predicted to result in premature protein termination (p.Tyr1563*). This variant has previously been reported to be causative for hereditary breast and ovarian cancer (Serova et al. 1996. PubMed ID: 8554067; Pern et al. 2012. PubMed ID: 23110154). This variant has also been recorded as a breast cancer associated variant within the Breast Cancer Information Core (BIC) database (http://research.nhgri.nih.gov/projects/bic/) and as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37607/). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41223242-G-C). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031188	SCV000839898	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-06	criteria provided, single submitter	clinical testing	The c.4689C>G (p.Tyr1563*) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 8554067, 23110154]. This variant creates a premature stop codon at amino acid position 1563 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 is thus classified as pathogenic.
Snyder Lab, Genetics Department, Stanford University	RCV000031188	SCV000853089	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159994	SCV000888922	pathogenic	not provided	2019-08-28	criteria provided, single submitter	clinical testing	This variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 29907814 (2018), 28324225 (2017), 8554067 (1996)). The frequency of this variant in the general population, 0.0000088 (1/113148 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159994	SCV001157089	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	The BRCA1 c.4689C>G; p.Tyr1563Ter variant (rs80357433), also known as 4808C>G, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer (Pern 2012, Rebbeck 2018, Schneegans 2012, Serova 1996). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Pern F et al. Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. PLoS One. 2012;7(10):e47993. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Schneegans SM Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012 Jun;11(2):181-8. Serova O et al. A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. Am J Hum Genet. 1996 Jan;58(1):42-51.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031188	SCV001440857	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-27	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159994	SCV001450206	pathogenic	not provided	2017-02-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159994	SCV001715198	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	PP5, PM2, PS4_moderate, PVS1
CeGaT Center for Human Genetics Tuebingen	RCV000159994	SCV001747802	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159994	SCV001905671	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000159994	SCV002009436	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159994	SCV002024610	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159994	SCV002550967	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000031188	SCV002580873	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-10-21	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000031188	SCV002761615	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-01-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031188	SCV004215019	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-24	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031188	SCV000053788	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031188	SCV000145160	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	RCV000048631	SCV000587421	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000159994	SCV000591537	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031188	SCV000733607	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785416	SCV000923988	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031188	SCV002588816	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing