Submissions for variant NM_007294.4(BRCA1):c.3700_3704del (p.Val1234fs)

dbSNP: rs80357609

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)	RCV000031123	SCV000282314	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	RCV000048287	SCV000076300	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1234Glnfs*8) 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 (PMID: 15024741, 18489799, 21324516, 23479189, 24010542, 25066507). This variant is also known as 3819del5. ClinVar contains an entry for this variant (Variation ID: 37542). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131816	SCV000186871	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	clinical testing	The c.3700_3704delGTAAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 5 nucleotides at nucleotide positions 3700 to 3704, causing a translational frameshift with a predicted alternate stop codon (p.V1234Qfs*8). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Takahashi H et al. Cancer Res., 1995 Jul;55:2998-3002; Serova O et al. Am J Hum Genet, 1996 Jan;58:42-51; Górski B et al. Am J Hum Genet, 2000 Jun;66:1963-8; Bergthorsson JT et al. J Med Genet, 2001 Jun;38:361-8; Foretova L et al. Hum Mutat, 2004 Apr;23:397-8; Ratajska M et al. Oncol Rep, 2008 Jan;19:263-8; Machackova E et al. BMC Cancer, 2008 May;8:140; Iyevleva AG et al. Cancer Lett, 2010 Dec;298:258-63; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Heidemann S et al. Breast Cancer Res Treat, 2012 Aug;134:1229-39; Ledwo JK et al. BMC Cancer, 2013 Oct;13:510; de Juan Jiménez I et al. Fam Cancer, 2013 Dec;12:767-77; Janaviius R et al. Cancer Genet, 2014 May;207:195-205; Meisel C et al. Arch Gynecol Obstet, 2017 May;295:1227-1238; Park B et al. Breast Cancer Res Treat, 2017 May;163:139-150; Zidekova D et al. Neoplasma;65:309-315; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Jakimovska M et al. Breast Cancer Res Treat, 2018 Apr;168:745-753; Rechsteiner M et al. J. Cancer Res. Clin. Oncol., 2018 May;144:865-874; Kluz T et al. Hered Cancer Clin Pract, 2018 Mar;16:6; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Koczkowska M et al. Cancers (Basel), 2018 Nov;10; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Rogoa-Janiszewska E et al. Cancers (Basel), 2020 Aug;12; Yildiz Tacar S et al. Life Sci, 2020 Nov;261:118334; Zografos E et al. BMC Cancer, 2021 May;21:572). This mutation has also been reported in a case study of a 74-year old male patient with a metastasized combined adeno-neuroendocrine carcinomas (MANEC) of the small bowel (Quaas A et al. BMC Gastroenterol, 2018 May;18:75). Of note, this alteration is also designated as c.3700_3704del5, 3819del5, and "3820-3824 5bp deletion" 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	RCV000235915	SCV000292517	pathogenic	not provided	2021-11-17	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 Hereditary Breast and Ovarian Cancer syndrome and described as a recurrent variant in Eastern European individuals (Foretova 2004, Foretova 2010, Schneegans 2012, de Juan Jimenez 2013, Ratajska 2015); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3695_3699delGTAAA, 3819_3823delGTAAA, and 3819del5; This variant is associated with the following publications: (PMID: 26843898, 25452441, 21324516, 7606717, 21503673, 22535016, 26083025, 10952777, 23479189, 15024741, 21348412, 27167707, 28205045, 25366421, 22160602, 27836010, 24171766, 29339979, 29335924, 28324225, 30322717, 31159747, 18097605, 30702160, 30078507, 31528241, 32719484, 32846166, 32341426, 31742824, 32295079, 34011307)
GeneKor MSA	RCV000238864	SCV000296798	pathogenic	Familial cancer of breast	2021-01-09	criteria provided, single submitter	clinical testing	This sequence change deletes 5 nucleotides in exon 11 of BRCA1 mRNA (c.3700_3704delGTAAA), causing a frameshift at codon 1234 and the creation of a premature translation stop signal 8 amino acid residues later p.(Val1234Glnfs*8). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This sequence change has been reported in the international literature in multiple families with Hereditary Breast and Ovarian Cancer syndrome and has been suggested to be a common BRCA1 variant in the Czech Republic (PMID: 15024741 ;22160602 ).This mutation has been described in the mutation database ClinVar (Variation ID: 37542).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031123	SCV000325727	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031123	SCV000488333	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-03	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031123	SCV000564379	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-15	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000048287	SCV000586894	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235915	SCV000600345	pathogenic	not provided	2020-09-24	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In the published literature, it has been reported in patients with breast/ovarian cancer and is described as a common mutation in individuals with Polish ancestry (PMID: 29335924 (2018), 28205045 (2017), 26843898 (2016), 22535016 (2012), 21324516 (2011)). Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048287	SCV000605765	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-13	criteria provided, single submitter	clinical testing	The p.Val1234fs variant in BRCA1 has been reported in >60 individuals with BRCA1 -associated cancers (Brozek 2011, Ratajska 2015, Breast Cancer Information Core (BIC)), and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1234 and leads to a premature termination codon 8 amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protein . Heterozygous loss of function of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-appro ved ENIGMA expert panel (ClinVar SCV000282314.1). In summary, the p.Val1234fs va riant meets criteria to be classified as pathogenic for HBOC in an autosomal dom inant manner.
Color Diagnostics, LLC DBA Color Health	RCV000131816	SCV000683123	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This variant deletes 5 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 3819del5 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 7606717, 8554067, 11389159, 11802209 , 18489799, 20727672, 21324516, 23479189, 24171766, 24010542, 25366421, 28205045, 29335924, 33670479, 34072659) and has been described as a recurrent or founder mutation in the Czech Republic, Germany, Poland, Kosovo and Russia (PMID: 22864640, 23199084, 26843898, 36171877, 36299383, 36367610, 37147448). This variant was found to segregate with breast and ovarian cancer affected members in one large pedigree (PMID: 8554067). A large breast cancer case-control study (PMID: 33471991) has reported this variant in 10/60456 cases, 1/53460 controls; OR=8.843 (95%CI 1.132 to 69.082); p-value=0.013; Leiden Open Variation Database DB-ID BRCA1_001454. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048287	SCV000699059	pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-26	criteria provided, single submitter	clinical testing	Variant summary: The c.3700_3704delGTAAA (p.Val1234Glnfs) variant in BRCA1 gene is a frameshift change that is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (~121382 and 246014 chrs tested). The variant of interest has been reported in multiple affected individuals and was shown to segregate with the disease within the family. Multiple reputable databases/clinical laboratories and published reports cited the variant as pathogenic. Taking together, the variant was classified as Pathogenic.
Mendelics	RCV000031123	SCV001140547	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000425	SCV001157235	pathogenic	not specified	2019-04-26	criteria provided, single submitter	clinical testing	The BRCA1 c.3700_3704del; p.Val1234fs variant (rs80357609), also known as 3819del5, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer, and is described as a recurrent BRCA1 variant in Eastern European individuals (Brozek 2011, Foretova 2004, Gorski 2000, Heramb 2018, Konstantopoulou 2014, Machackova 2008, Ratajska 2008, Takahashi 1995). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37542), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 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: Brozek I et al. Prevalence of the most frequent BRCA1 mutations in Polish population. J Appl Genet. 2011 Aug;52(3):325-30. Foretova L et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr;23(4):397-8. Gorski B et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000 Jun;66(6):1963-8. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Konstantopoulou I et al. High prevalence of BRCA1 founder mutations in Greek breast/ovarian families. Clin Genet. 2014 Jan;85(1):36-42. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. Ratajska M et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep. 2008 Jan;19(1):263-8. Takahashi H et al. Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res. 1995 Jul 15;55(14):2998-3002.
CeGaT Center for Human Genetics Tuebingen	RCV000235915	SCV001247353	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PP1
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031123	SCV001429221	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-04-10	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000235915	SCV001450231	pathogenic	not provided	2014-07-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000235915	SCV001480186	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000031123	SCV001499718	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	RCV000235915	SCV002009450	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131816	SCV002538230	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000031123	SCV002581454	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-07-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000235915	SCV003811733	pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031123	SCV004212743	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235915	SCV004224883	pathogenic	not provided	2023-02-08	criteria provided, single submitter	clinical testing	PP1, PM2, PS4_moderate, PVS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235915	SCV004242820	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031123	SCV004817763	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-08	criteria provided, single submitter	clinical testing	This variant deletes 5 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 3819del5 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 7606717, 8554067, 11389159, 11802209 , 18489799, 20727672, 21324516, 23479189, 24171766, 24010542, 25366421, 28205045, 29335924, 33670479, 34072659) and has been described as a recurrent or founder mutation in the Czech Republic, Germany, Poland, Kosovo and Russia (PMID: 22864640, 23199084, 26843898, 36171877, 36299383, 36367610, 37147448). This variant was found to segregate with breast and ovarian cancer affected members in one large pedigree (PMID: 8554067). A large breast cancer case-control study (PMID: 33471991) has reported this variant in 10/60456 cases, 1/53460 controls; OR=8.843 (95%CI 1.132 to 69.082); p-value=0.013; Leiden Open Variation Database DB-ID BRCA1_001454. 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031123	SCV005045942	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM2_supporting; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000235915	SCV005198128	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031123	SCV000053721	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031123	SCV000144839	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	RCV000048287	SCV000587333	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353692	SCV000591463	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785409	SCV000923981	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
CZECANCA consortium	RCV001271015	SCV001451827	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001564012	SCV001786709	pathogenic	Abnormality of the ovary	2021-08-16	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001579304	SCV001805838	pathogenic	Ovarian carcinoma	2021-08-21	no assertion criteria provided	clinical testing	high grade serous carcinoma
BRCAlab, Lund University	RCV000031123	SCV002589109	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing