Submissions for variant NM_007294.4(BRCA1):c.1687C>T (p.Gln563Ter)

gnomAD frequency: 0.00001  dbSNP: rs80356898

Total submissions: 55

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031007	SCV000282262	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	RCV000047559	SCV000075572	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln563*) 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 (rs80356898, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and pancreatic cancer (PMID: 21989927, 23199084, 24312913, 25330149, 25948282, 26852130). This variant is also known as 1806C>T. ClinVar contains an entry for this variant (Variation ID: 37426). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131897	SCV000186952	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-26	criteria provided, single submitter	clinical testing	The p.Q563* pathogenic mutation (also known as c.1687C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1687. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in numerous patients and families with hereditary breast and ovarian cancer (HBOC) syndrome (Shattuck-Eidens D et al. JAMA. 1995 Feb;273:535-41; Ghiorzo P et al. Fam. Cancer. 2012 Mar;11:41-7; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Finch A et al. Clin. Genet. 2016 Mar;89:304-11; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Cotrim DP et al. BMC Cancer. 2019 Jan;19(1):4). This alteration has been described as a European founder mutation, having been detected in Austrian, Slovenian, Swedish and Polish populations (Janaviius R. EPMA J. 2010 Sep;1:397-412; Kluska A et al. BMC Med. Genomics. 2015 May;8:19). Of note, this alteration is also designated as 1806C>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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031007	SCV000195893	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000159956	SCV000210108	pathogenic	not provided	2020-05-11	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 (Janavicius 2010, Ghiorzo 2012, Karami 2013, Meisel 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 1806C>T; This variant is associated with the following publications: (PMID: 24312913, 15024741, 15876480, 20373018, 21989927, 22776961, 24504028, 12566964, 11504767, 9663595, 23397983, 25948282, 26852130, 25525159, 18439106, 26843898, 27003155, 27376475, 27425403, 27194814, 7837387, 27914478, 27741520, 27836010, 28123851, 28127413, 28166811, 28281021, 28324225, 26681312, 28857155, 29339979, 29335924, 29907814, 29346284, 11251181, 29161300, 30103829, 30606148, 29446198, 30720243, 30322717, 31589614, 32341426, 33087929, 23199084)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159956	SCV000296341	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	The BRCA1 c.1687C>T (p.Gln563*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in numerous individuals with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 26219728 (2016), 27425403 (2016), 27741520 (2016), 29335924 (2018), 33478551 (2021), 33670479 (2021), 38386807 (2024), 38785549 (2024)), as well as in individuals with pancreatic (PMIDs: 21989927 (2012), 32073954 (2020)), bladder (PMIDs: 32073954 (2020), 32073954 (2022)), and cervical cancer (PMID: 36451132 (2022)). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000238721	SCV000296792	pathogenic	Ovarian cancer	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031007	SCV000325122	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415155	SCV000492951	pathogenic	Ovarian neoplasm; Breast carcinoma	2014-02-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131897	SCV000537661	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-17	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 has been reported in individuals affected with breast and/or ovarian cancer and in hereditary breast and ovarian cancer families (PMID: 20373018, 23479189, 24504028, 24728189, 25066507, 25330149, 26083025, 26219728, 26350514, 26852130, 27425403, 27741520, 28324225, 29335924, 30606148, 36367610, 38386807, 38785549, 38922859). This variant also has been detected in a breast cancer case-control meta-analysis in 12/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000161). This variant has been identified in 7/250426 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.
Department of Medical Genetics, Oslo University Hospital	RCV000031007	SCV000564338	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000031007	SCV000577923	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047559	SCV000698881	pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-14	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1687C>T (p.Gln563X) 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. This variant was found in 5/121138 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). These occurrences need to be cautiously considered due to the cohort could harbor individuals with a BRCA1 phenotype. This variant has been reported in multiple HBOC patients and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000047559	SCV000839281	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763006	SCV000893451	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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770747	SCV000902230	pathogenic	Breast and/or ovarian cancer	2016-05-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047559	SCV000966957	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Gln563X variant in BRCA1 (also referred to as 1806C>T) has been reported in >100 individuals with BRCA1-associated cancers (Shattuck-Eidens 1995, Wagner 1998, Pohlreich 2003, Foretova 2004, Salazar 2006, Krajc 2008, Janav 2010, Zuradelli 2010, Blay 2013, Cunningham 2014, Kluska 2015, Cini 2016, Breast Cancer Information Core (BIC) database). It was also identified in 5/66568 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356898); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 563, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in HBOC. Furthermore, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282262.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. PVS1, PM2, PS4.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000786987	SCV001370480	pathogenic	Familial cancer of breast	2019-12-12	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031007	SCV001428855	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-01-26	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4
Institute of Genomics, University of Tartu	RCV000031007	SCV001430696	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159956	SCV001447437	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159956	SCV001449782	pathogenic	not provided	2014-10-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159956	SCV001472137	pathogenic	not provided	2019-07-26	criteria provided, single submitter	clinical testing	The BRCA1 c.1687C>T; p.Gln563Ter variant (rs80356898), also known as 1806C>T, has been reported in multiple individuals with breast and/or ovarian cancer (Cunningham 2014, Maistro 2016, Shattuck-Eidens 1995, Wagner 1998). It is listed as pathogenic in ClinVar (Variation ID: 37426), and observed 6 times in the Genome Aggregation Database population database (6/245302 alleles). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Maistro S et al. Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer. 2016; 16(1):934. Shattuck-Eidens D et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995; 273(7):535-41. Wagner T et al. BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics. Int J Cancer. 1998; 77(3):354-60.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000031007	SCV001499621	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000159956	SCV002009464	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159956	SCV002024588	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159956	SCV002063621	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
DASA	RCV000031007	SCV002107121	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-05	criteria provided, single submitter	clinical testing	The c.1687C>T;p.(Gln563*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 12393792) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37426; PMID: 23199084; PMID: 24312913; PMID: 21989927; PMID: 25330149; PMID: 25948282; PMID: 26852130; PMID: 12393792) - PS4. The variant is present at low allele frequencies population databases (rs80356898 – gnomAD 0.0002795%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Department of Human Genetics, Hannover Medical School	RCV000031007	SCV002318989	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-30	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000031007	SCV002512508	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-07-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PVS1, PS3 supporting, PS4 strong, PS4, PM2
Genetics Program, Instituto Nacional de Cancer	RCV000047559	SCV002515176	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131897	SCV002538045	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159956	SCV002551031	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000031007	SCV002762792	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-09	criteria provided, single submitter	research	PVS1, PS3, PS4_STR
Human Genetics Bochum, Ruhr University Bochum	RCV000031007	SCV004042799	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-07	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP
Baylor Genetics	RCV000031007	SCV004215010	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802954	SCV004818298	pathogenic	BRCA1-related cancer predisposition	2024-09-13	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 has been reported in individuals affected with breast and/or ovarian cancer and in hereditary breast and ovarian cancer families (PMID: 20373018, 23479189, 24504028, 24728189, 25066507, 25330149, 26083025, 26219728, 26350514, 26852130, 27425403, 27741520, 28324225, 29335924, 30606148, 36367610, 38386807, 38785549, 38922859). This variant also has been detected in a breast cancer case-control meta-analysis in 12/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000161). This variant has been identified in 7/250426 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031007	SCV005045929	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000159956	SCV005199747	pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031007	SCV000053600	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031007	SCV000144157	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031007	SCV000211992	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	RCV000047559	SCV000587157	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000159956	SCV000591346	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Gln563* variant was identified in 13 of 4212 proband chromosomes (frequency: 0.003) from individuals or families with breast or ovarian cancer and was present in 1 of 2600 control chromosomes (frequency: 0.0004) from healthy individuals (Alemar 2016, Cybulski 2015, Fernandes 2016, Jakimovska 2018, Kluska 2015, Maistro 2016, Meisel 2017). The variant was also identified in dbSNP (ID: rs80356898) as "With Pathogenic allele", ClinVar (classified as pathogenic by 23 submitters), LOVD 3.0 (49x as pathogenic), and UMD-LSDB (12x as causal). The variant was identified in control databases in 6 of 245302 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 6 of 111186 chromosomes (freq: 0.00005), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1687C>T variant leads to a premature stop codon at position 563, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in HBOC and is the type of variant expected to cause the disorder. In addition, one study demonstrated that this variant results in nonsense-mediated decay (Perrin-Vidoz 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031007	SCV000733653	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	RCV000785207	SCV000923775	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786987	SCV000925893	pathogenic	Familial cancer of breast	2018-11-23	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV000770747	SCV001451771	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000159956	SCV001906050	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159956	SCV001956616	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000159956	SCV001974923	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031007	SCV002589085	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128130	SCV003804344	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554614	SCV004733048	pathogenic	BRCA1-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The BRCA1 c.1687C>T variant is predicted to result in premature protein termination (p.Gln563*). This variant (also known as c.1806C>T in the literature) has been reported to be causative for breast, ovarian, and pancreatic cancer (Shattuck-Eidens et al. 1995. PubMed ID: 7837387; Susswein et al. 2016. PubMed ID: 26681312, Table S1; Ghiorzo et al. 2012. PubMed ID: 21989927; Schrader et al. 2012. PubMed ID: 22776961). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37426/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031007	SCV005061279	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control