Submissions for variant NM_007294.4(BRCA1):c.3770_3771del (p.Glu1257fs)

dbSNP: rs80357579

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031127	SCV000300013	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	RCV000048325	SCV000076338	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) 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 (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131814	SCV000186869	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	clinical testing	The c.3770_3771delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon (p.E1257Gfs*9). This mutation has been reported in multiple breast and ovarian cancer families to date (Couch FJ et al. Hum. Mutat., 1996;8:8-18; Liede A et al. Am. J. Hum. Genet., 2002 Sep;71:595-606; Blay P et al. BMC Cancer, 2013 May;13:243; Rashid MU et al. BMC Cancer, 2016 08;16:673; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Cock-Rada AM et al. Fam Cancer, 2018 01;17:23-30; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Li JY et al. Int J Cancer, 2019 01;144:281-289; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Feng Z et al. Ann Transl Med, 2021 Mar;9:364). Of note, this alteration is also designated as 3889delAG 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	RCV000235232	SCV000292519	pathogenic	not provided	2022-11-22	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Takahashi 1995, Liede 2002, Esteban Cardeosa 2010, Sakamoto 2016, Manchana 2019, Rashid 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3889_3890delAG; This variant is associated with the following publications: (PMID: 25802882, 16758124, 11597388, 28127413, 28477318, 30078507, 29922827, 28888541, 29884136, 33858029, 7606717, 12181777, 20033483, 26439132, 30350268, 32318955, 8807330, 11106241, 24289553, 26026974, 26757417, 19941167, 23317271, 17076205, 23683081, 21559243, 20960228, 26911350, 27983536, 27393621, 27836010, 26848529, 27553291, 29215753, 28176296, 29093764, 28152038, 27062684, 28528518, 29339979, 29752822, 29907814, 29470806, 28724667, 28993434, 30675318, 30702160, 30720863, 30720243, 30972954, 23479189, 31815095, 31528241, 31957001, 31447099, 31589614, 32341426, 31825140, 32885271, 33151324, 31742824, 34645131, 35377489)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235232	SCV000296287	pathogenic	not provided	2021-04-21	criteria provided, single submitter	clinical testing	The BRCA1 c.3770_3771del (p.Glu1257Glyfs*9) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast or ovarian cancer (PMID: 23479189 (2013), 30972954 (2019), 31957001 (2020); BRCA Exchange (http://brcaexchange.org/)). The frequency of this variant in the general population, 0.000087 (1/11484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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	RCV000031127	SCV000325752	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031127	SCV000488193	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-01-19	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031127	SCV000564304	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000031127	SCV000577929	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131814	SCV000683133	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 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 is also known as 3889delAG and 3888delGA in the literature according to the BIC nomenclature. This variant has been reported in over thirty individuals affected with breast and/or ovarian cancer (PMID: 18627636, 23479189, 23683081, 26026974, 26757417, 26824983, 27553291, 28176296, 28528518, 29339979). This variant has been identified in 2/251226 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	RCV000031127	SCV000744624	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677799	SCV000803957	pathogenic	Ovarian cancer	2017-06-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048325	SCV000918771	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3770_3771delAG (p.Glu1257GlyfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251226 control chromosomes (gnomAD). c.3770_3771delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Takahashi_1995, Judkins_2005, Hansa_2012, Thirthagiri_2008, Sun_2017). 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: 16267036, 18627636, 7606717, 23317271, 28724667). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031127	SCV001434963	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-10-08	criteria provided, single submitter	clinical testing	The c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 7606717, 16683254, 17319787, 18627636, 23479189, 27553291). This variant has an extremely low frequency in large databases of genetic variation in the general population. Therefore, the c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000235232	SCV001450255	pathogenic	not provided	2014-11-27	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000048325	SCV002515205	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Arcensus	RCV000031127	SCV002564555	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-02-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235232	SCV002760931	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000235232	SCV003809158	pathogenic	not provided	2021-12-17	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031127	SCV003923322	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-01	criteria provided, single submitter	clinical testing	A known pathogenic mutation was detected in the BRCA1 gene(p.Glu1257fs).his sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) 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 (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing.
Baylor Genetics	RCV000031127	SCV004212772	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-07	criteria provided, single submitter	clinical testing
OMIM	RCV000031127	SCV000039545	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-08-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000031127	SCV000053726	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-23	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031127	SCV000144872	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	RCV000048325	SCV000587347	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031127	SCV000733617	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	RCV000785411	SCV000923983	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000235232	SCV001549686	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Glu1257Glyfs*9 variant was identified in 27 of 18350 proband chromosomes (frequency: 0.0015) from individuals or families with breast or ovarian cancer (Blay 2013, Chen 2009, Cock-Rada 2018, de Juan Jimenez 2013, Heramb 2018, Hirotsu 2014, Konecny 2007, Thirthagiri 2008, van der Hout 2006). The variant was also identified in the following databases: dbSNP (ID: rs80357993) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and fourteen other submitters), COGR, LOVD 3.0 (28x), UMD-LSDB (25x causal), BIC Database (23x with clinical importance), ARUP Laboratories (definitely pathogenic), and in Zhejiang University database (2x). The variant was not identified in Cosmic or MutDB databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3770_3771del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1257 and leads to a premature stop codon at position 1265. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in breast and ovarian cancer 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.
CZECANCA consortium	RCV001391223	SCV001593139	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554258	SCV001774865	pathogenic	Breast carcinoma	2021-08-09	no assertion criteria provided	clinical testing
Cancer Genomics Lab, PINUM Cancer Hospital	RCV000048325	SCV004011748	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-03	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031127	SCV004244026	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing