Submissions for variant NM_007294.4(BRCA1):c.5030_5033del (p.Thr1677fs)

dbSNP: rs80357580

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031204	SCV000300187	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.
Invitae	RCV000048741	SCV000076754	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1677Ilefs*2) 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 and/or ovarian cancer, and pancreatic cancer (PMID: 9150149, 21989927, 22144684, 22160602). This variant is also known as 5149del4, ter1678 and c.5149delCTAA. ClinVar contains an entry for this variant (Variation ID: 37623). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031204	SCV000195936	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162882	SCV000213369	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	The c.5030_5033delCTAA pathogenic mutation, located in coding exon 15 of the BRCA1 gene, results from a deletion of 4 nucleotides at positions 5030 to 5033, causing a translational frameshift with a predicted alternate stop codon (p.T1677Ifs*2). This mutation has been reported in numerous HBOC families and patients with triple negative breast cancer throughout the world (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60(5):1021-30; Caputo S et al. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002; Ghiorzo P et al. Fam. Cancer 2012 Mar;11(1):41-7; Schneegans SM et al. Fam. Cancer 2012 Jun;11(2):181-8; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151(1):157-68; Dodova RI et al. BMC Cancer 2015 Jul;15:523; Rashid M et al. BMC Cancer 2016 08;16(1):673; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Abdel-Razeq H et al. BMC Cancer 2018 02;18(1):152). Of note, this alteration is also designated as 5149del4 and 5149delCTAA 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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240792	SCV000265866	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
GeneDx	RCV000236835	SCV000292525	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Stoppa-Lyonnet et al., 1997; Schneegans et al., 2012; Solano et al., 2012; de Juan Jimenez et al., 2013; Kang et al., 2015; Rweyemamu et al., 2023); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5149_5152delCTAA; This variant is associated with the following publications: (PMID: 28127413, 22160602, 25863477, 30702160, 30287823, 34290354, 34490083, 34413315, 32455662, 32980694, 32772980, 32438681, 30040829, 28888541, 9150149, 22144684, 21989927, 23961350, 23479189, 26183948, 24916970, 15146557, 26843898, 26083025, 27741520, 22798144, 27553291, 27062684, 29020732, 29339979, 29752822, 28831036, 29907814, 28111427, 31372034, 30309222, 30199306, 32072338, 29625052, 26689913, 33726785, 11597388, 32341426, 32719484, 30875412, 30787465, 30613976, 36139606, 34645131, 35264596, 34063308, 34072659, 36230495, 33403015, 32245699, 32380732, 35908255, 35451682, 35893033, 34657357, 35216584, 33649982, 32694901, 34022715, 32862574)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236835	SCV000296478	pathogenic	not provided	2021-08-09	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In addition, it has been reported in affected individuals with breast and/or ovarian cancer and has been reported as a founder variant in French breast cancer populations (PMIDs: 31372034 (2019), 30128899 (2018), 29907814 (2018), 22144684 (2012), and 9150149 (1997)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031204	SCV000326110	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031204	SCV000564386	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162882	SCV000683243	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 16 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 11 individuals affected with breast and/or ovarian cancer (PMID: 22160602, 22798144, 23961350, 23479189, 24916970, 25863477, 29339979, 29409476, 29752822, 29907814, 30128899, 33471991). This variant has not been identified 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	RCV000031204	SCV000744603	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031204	SCV000785273	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000048741	SCV000839222	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048741	SCV000916746	pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5030_5033delCTAA (p.Thr1677IlefsX2) 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 was absent in 251382 control chromosomes. c.5030_5033delCTAA has been reported in the literature in numerous individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 13 clinical submitters via ClinVar have classified the variant as pathogenic, including an expert panel. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236835	SCV001446761	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	RCV000031204	SCV001519672	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490431	SCV002792367	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-11-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031204	SCV004212753	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000236835	SCV004224816	pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing	PP5, PM2, PS4_moderate, PVS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000236835	SCV004563523	pathogenic	not provided	2023-11-06	criteria provided, single submitter	clinical testing	The BRCA1 c.5030_5033del; p.Thr1677IlefsTer2 variant (rs80357580), also known as 5149del4 or c.5149delCTAA, is reported in the literature in many individuals affected with breast and/or ovarian cancer, and is reported as a founder variant in the French population (selected publications: Caputo 2012, Guindalini 2022, Kechin 2023, Li 2019, Stoppa-Lyonnet 1997). This variant is also reported in ClinVar (Variation ID: 37623), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it 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: Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. PMID: 22144684. Guindalini RSC et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci Rep. 2022 Mar 9;12(1):4190. PMID: 35264596. Kechin A et al. A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia. Breast Cancer Res Treat. 2023 Jan;197(2):387-395. PMID: 36367610. Li JY et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. PMID: 29752822. Stoppa-Lyonnet D et al. BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. Am J Hum Genet. 1997 May;60(5):1021-30. PMID: 9150149.
Sharing Clinical Reports Project (SCRP)	RCV000031204	SCV000053804	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031204	SCV000145266	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	RCV000048741	SCV000587444	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353650	SCV000591562	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Thr1677IlefsX2 deletion variant was identified in 39 of 56694 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Caputo 2011, Ghiorzo 2012, Solano 2012, Stoppa-Lyonnet 1997, van der Hout 2006). This variant was also identified in the following databases: dbSNP (ID: rs80357862) “With pathogenic allele”, LOVD, UMD (59X as a causal variant), and BIC (17X with clinical importance). The p.Thr1677IlefsX2 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1677 and leads to a premature stop codon at position 1678. This alteration is then predicted to result in a truncated or absent protein and loss of function, and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735512	SCV000863650	pathogenic	Breast and/or ovarian cancer	2013-11-04	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000236835	SCV001739788	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000236835	SCV001905851	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031204	SCV002588820	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162264	SCV002758466	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Research and Experiment Center, Meizhou People's Hospital	RCV002513283	SCV003760906	pathogenic	Familial cancer of breast		no assertion criteria provided	clinical testing