Submissions for variant NM_007294.4(BRCA1):c.3756_3759del (p.Ser1253fs)

dbSNP: rs80357868

Total submissions: 51

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019242	SCV000282317	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	RCV000167859	SCV000076327	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1253Argfs*10) 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 (rs80357868, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 7894491, 21324516, 21989927, 23633455). This variant is also known as 3875del4. ClinVar contains an entry for this variant (Variation ID: 17673). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131810	SCV000186865	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-11	criteria provided, single submitter	clinical testing	The c.3756_3759delGTCT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3756 to 3759, causing a translational frameshift with a predicted alternate stop codon (p.S1253Rfs*10). This recurrent mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families globally (Castilla LH et al. Nat. Genet. 1994 Dec;8:387-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Tedaldi G et al. Oncotarget. 2017 Jul;8:47064-47075; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Bhaskaran SP et al. Int. J. Cancer. 2019 Jan;[Epub ahead of print]). Of note, this alteration is also designated as 3875del4 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	RCV000048314	SCV000210046	pathogenic	not provided	2019-12-06	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; 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 (Lek 2016); This variant is associated with the following publications: (PMID: 21324516, 23621881, 24504028, 27533253, 29310832, 23199084, 31447099, 12947551, 7894491, 23633455, 22711857, 21989927, 27003155, 26779294, 22864640, 25085752, 27356891, 27836010, 27225819, 26843898, 27157322, 27383479, 27062684, 29339979, 28724667, 28423363, 28176296, 30702160, 30720243, 30535581, 31090900, 31159747, 30078507, 30128899, 30103829, 30322717, 26681312, 30093976, 30972954, 31472684, 32388397)
Counsyl	RCV000019242	SCV000220913	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-24	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000131810	SCV000292139	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3875_3878delGTCT, 3875del4, 3875delGTCT in the literature based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 16168118, 21324516, 21989927, 22711857, 23633455) and pancreatic cancer (PMID: 21989927), and has been described as a common cause of hereditary breast-ovarian cancer in the French-Canadian population (PMID: 23199084). A breast cancer case-control meta-analysis reported this variant in 15/60466 cases and 2/53461 unaffected individuals with OR=6.633 (95%CI 1.517 to 29.005) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000278). This variant has been identified in 6/251272 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048314	SCV000296325	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	The BRCA1 c.3756_3759del (p.Ser1253Argfs*10) variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 33471991 (2021), 29339979 (2018), 11183185 (2000), 8531967 (1996)), ovarian cancer (PMID: 33287145 (2020), 30078507 (2018), 21324516 (2011)), and pancreatic cancer (PMID: 21989927 (2012)). This variant has also been described as a French founder mutation (PMID: 23199084 (2010)). The frequency of this variant in the general population, 0.000044 (5/113572 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000239051	SCV000296799	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes 4 nucleotide from exon 11 of the BRCA1 mRNA (c.3756_3759delGTCT), causing a frameshift after codon 1253 and the creation of a premature translation stop signal 10 amino acid residues later- p.(Ser1253Argfs*10). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant has been reported in the literature in individuals with inherited breast and/or ovarian cancer, and prostate cancer (PMID: 7894491, 21324516). This variant is also as 3875del4 in the literature.This mutation has been described in the mutation database ClinVar (Variation ID:17673).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019242	SCV000325742	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019242	SCV000564358	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-10	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000019242	SCV000577928	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	RCV000167859	SCV000699069	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-22	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3756_3759delGTCT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1756fs). Mutation Taster predicts a damaging outcome for this variant. This variant was found in 3/121438 control chromosomes at a frequency of 0.0000247, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant has been cited in multiple HBOC patients in the literature. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000019242	SCV000744625	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	RCV000019242	SCV000839892	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-11-01	criteria provided, single submitter	clinical testing	The c.3756_3759delGTCT (p.Ser1253Argfs*10) frame shift variant is predicted to yield loss of function transcripts/proteins of BRCA1 gene, which is one of mechanisms causing BRCA1 defect related cancers. This variant is extremely rare in general population (4 in 246010 by gnomad) and observed in multiple breast/ovarian cancer patients (PMID:78944991, 12947551, 21324516, 23633455, 24504028). It has been also observed in other clinical labs and reported as pathogenic. Based on the above evidences, we interpret this variant as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000019242	SCV000993437	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-25	criteria provided, single submitter	research
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000167859	SCV001251937	pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-03	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000019242	SCV001251951	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-05-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167859	SCV001365789	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-08	criteria provided, single submitter	clinical testing	The p.Ser12353ArgfsX10 variant in BRCA1 has been reported in >100 individuals with breast and/or ovarian cancer (George 2013, Ghiorzo 2012, Meindl 2002, Pohlreich 2005, Sun 2017, Susswein 2015, Zhang 2011, Breast Cancer Information Core (BIC) ). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar VCV000017673.2). This variant has been identified in 0.004% (5/113572) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1253 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019242	SCV001429279	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-09	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000048314	SCV001446820	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000048314	SCV001450000	pathogenic	not provided	2017-10-17	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000019242	SCV001499716	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000048314	SCV001716303	pathogenic	not provided	2019-06-13	criteria provided, single submitter	clinical testing	PVS1, PS4_Mod, PP5
CeGaT Center for Human Genetics Tuebingen	RCV000048314	SCV001747806	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000048314	SCV002009448	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000048314	SCV002021632	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735506	SCV002043441	pathogenic	Breast and/or ovarian cancer	2023-05-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131810	SCV002538243	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048314	SCV002550989	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000019242	SCV002579565	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-01-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000019242	SCV004171323	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000019242	SCV004175583	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-02-25	criteria provided, single submitter	clinical testing	The BRCA1 c.3756_3759delGTCT variant is classified as Pathogenic (PVS1, PM2, PP5_Moderate) This BRCA1 c.3756_3759delGTCT variant is predicted to cause a shift in the reading frame at codon 1253, introducing a premature termination codon (PVS1). The variant has been reported in dbSNP (rs80357868) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 17673). It has not been reported in HGMD.
Baylor Genetics	RCV000019242	SCV004212771	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000019242	SCV004817751	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-11	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3875_3878delGTCT, 3875del4, 3875delGTCT in the literature based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 16168118, 21324516, 21989927, 22711857, 23633455) and pancreatic cancer (PMID: 21989927), and has been described as a common cause of hereditary breast-ovarian cancer in the French-Canadian population (PMID: 23199084). A breast cancer case-control meta-analysis reported this variant in 15/60466 cases and 2/53461 unaffected individuals with OR=6.633 (95%CI 1.517 to 29.005) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000278). This variant has been identified in 6/251272 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	RCV000019242	SCV005045962	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	RCV000048314	SCV005197241	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000019242	SCV000039530	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019242	SCV000053723	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-11-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019242	SCV000144861	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000019242	SCV000212000	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-11	no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000239051	SCV000484932	pathogenic	Familial cancer of breast		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000167859	SCV000587342	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000167859	SCV000591471	pathogenic	Hereditary breast ovarian cancer syndrome		no assertion criteria provided	clinical testing	The p.Ser1253ArgfsX10 variant has been identified in 17 out of 6280 proband chromosomes (frequency 0.003) in individuals with breast and ovarian cancer phenotype, but not found in 200 control chromosomes included in these studies (Turner 1999, Langston 1996, Castilla 1994, Zhang 2011, Gaj 2012). It is also listed in dbSNP database presented “with untested allele” (ID#: rs80357868) while no frequency information is provided; however, this variant has been listed 27X in the UMD and 123X in the BIC database as a clinically significant mutation. The p.Ser1253ArgfsX10 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent BRCA1 protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000019242	SCV000733618	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735506	SCV000863644	pathogenic	Breast and/or ovarian cancer	2015-05-19	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000782127	SCV000916304	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ser1253ArgfsX10 variant has been identified in 17 out of 6280 proband chromosomes (frequency 0.003) in individuals with breast and ovarian cancer phenotype, but not found in 200 control chromosomes included in these studies (Turner 1999, Langston 1996, Castilla 1994, Zhang 2011, Gaj 2012). It is also listed in dbSNP database presented ?with untested allele? (ID#: rs80357868) while no frequency information is provided; however, this variant has been listed 27X in the UMD and 123X in the BIC database as a clinically significant mutation. The p.Ser1253ArgfsX10 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent BRCA1 protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785410	SCV000923982	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
CZECANCA consortium	RCV000735506	SCV001451828	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000048314	SCV001905794	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000239051	SCV002520869	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000019242	SCV004244028	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing