Submissions for variant NM_007294.4(BRCA1):c.4065_4068del (p.Asn1355fs)

dbSNP: rs80357508

Total submissions: 48

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019243	SCV000282322	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	RCV000048431	SCV000076444	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1355Lysfs*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 (rs80357508, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8571953, 11802209, 14757871, 21559243). It has also been observed to segregate with disease in related individuals. This variant is also known as 4184del4. ClinVar contains an entry for this variant (Variation ID: 17674). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131887	SCV000186942	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The c.4065_4068delTCAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 4065 to 4068, causing a translational frameshift with a predicted alternate stop codon (p.N1355Kfs*10). This alteration has been reported in multiple families with hereditary breast and ovarian cancer from a variety of ethnic backgrounds (Shattuck-Eidens D et al. JAMA. 1995 Feb;273:535-41; Langston AA et al. N. Engl. J. Med. 1996 Jan;334:137-42; Spitzer E et al. Int. J. Cancer. 2000 Feb;85:474-81; Ahn SH et al. Cancer Lett. 2007 Jan;245:90-5; Cunningham J et al. Sci. Rep. 2014 Feb;4:4026; Rashid MU et al. BMC Cancer. 2016 Aug;16:673; Li JY et al. Int. J. Cancer 2019 Jan;144(2):281-289; Siraj AK et al. Hum. Mutat. 2019 Mar). This mutation was also identified in an individual from a cohort of 191 prostate cancer patients with at least three prostate cancer cases in their families; this individual's family was also noted to be affected with breast and colon cancer (Leongamornlet D et al. Br. J. Cancer. 2014 Mar;110:1663-72). Of note, this alteration is also designated as 4184del4 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	RCV000159924	SCV000210049	pathogenic	not provided	2020-04-06	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; Observed in many individuals with personal and/or family history consistent with pathogenic variants in this gene (Friedman 1994, Neuhausen 1996, Liede 2002, Meindl 2002, Farooq 2011, Couch 2015, Bu 2016, Chan 2018); Not observed at a 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; This variant is associated with the following publications: (PMID: 23633455, 24556621, 21559243, 11802209, 10699917, 26852015, 20104584, 25948282, 31957001, 25085752, 29348823, 29752822, 31372034, 30199306, 7894493, 8571953, 12181777, 25452441, 27082205, 30093976, 24504028, 2270482, 21324516, 17018160, 14757871, 23683081, 23175448, 24549055, 7894492, 8531967, 27157322, 16455195, 26997744, 26350514, 28127413, 27836010, 27553291, 28392550, 29907814, 29422015, 7837387, 28831036, 17100994, 29339979, 29470806, 28724667, 28993434, 30702160, 30078507, 28176296, 30720243, 30014164, 31174498, 30322717, 30825404, 31454914, 31528241, 29625052, 26689913, 29176636, 32029870, 31948886)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000048431	SCV000219238	pathogenic	Hereditary breast ovarian cancer syndrome	2017-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000019243	SCV000220878	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-14	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159924	SCV000296305	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer and ovarian cancer in the published literature (PMIDs: 29752822 (2018), 29470806 (2018), 28993434 (2018), 27553291 (2016), 28831036 (2017)). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000238776	SCV000296801	pathogenic	not specified	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019243	SCV000325829	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000476410	SCV000540939	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019243	SCV000564378	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000019243	SCV000577930	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Bioinformatics dept., Datar Cancer Genetics Limited, India	RCV000019243	SCV000584013	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131887	SCV000683147	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-14	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 expected to result in an absent or non-functional protein product. This is a recurrent variant detected in hereditary breast and ovarian cancer families worldwide and has been reported in at least 30 individuals affected with breast and/or ovarian cancer (PMID: 7894493, 8531967, 17018160, 16455195, 20104584, 21324516, 21559243, 23175448, 23633455, 27553291, 28724667, 28831036, 28993434, 29470806, 30078507, 29752822, 30825404, 33471991; Leiden Open Variation Database DB-ID BRCA1_000288) and an individual affected with prostate cancer (PMID: 24556621). This variant has been identified in 3/250844 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048431	SCV000699105	pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-22	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4065_4068delTCAA (p.Asn1355Lysfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.4117G>T, p.Glu1373X; c.4158_4162delCTCTC, p.Ser1387fs). This variant has been reported in numerous HBOC patients with positive family history (e.g. Langston 1996, Spitzer 2000, Evans 2004, Borg 2010). This variant is absent in 121322 control chromosomes, suggesting that it is not a common, benign variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000019243	SCV000744620	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000048431	SCV000839242	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Institute of Genomics, University of Tartu	RCV000019243	SCV001430691	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159924	SCV001447869	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159924	SCV001449903	pathogenic	not provided	2017-09-19	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000019243	SCV001499713	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159924	SCV002024667	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735453	SCV002043443	pathogenic	Breast and/or ovarian cancer	2020-03-25	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000019243	SCV002061853	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-06	criteria provided, single submitter	clinical testing	PVS1, PS4
Genetics and Molecular Pathology, SA Pathology	RCV000019243	SCV002556629	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-17	criteria provided, single submitter	clinical testing	The BRCA1 c.4065_4068del variant is classified as Pathogenic (PVS1, PS4_Supporting, PM2) This BRCA1 c.4065_4068del variant is located in exon 10/23 and is predicted to cause a shift in the reading frame at codon 1355. The variant is rare in population databases (PM2). The variant has been reported in dbSNP (rs80357508) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 17674). It has not been reported in HGMD. BRCA1:c.4065_4068del (also described as BRCA1 4184del4 using legacy nomenclature) has been reported in multiple unrelated individuals and families with breast, peritoneal, fallopian tube and ovarian cancer (Siraj et al., 2018 PMID: 30825404, Singh et al., 2018 PMID: 29470806; Heramb et al., 2018 PMID: 29339979; Li et al., 2019 PMID: 29752822).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019243	SCV002576402	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-17	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000019243	SCV002762799	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR
Fulgent Genetics, Fulgent Genetics	RCV002490392	SCV002800174	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-04-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159924	SCV004009793	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
Neuberg Centre For Genomic Medicine, NCGM	RCV000019243	SCV004047894	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The c.4065_4068del (p.Asn1355LysfsTer10) frameshift variant in BRCA1 gene has been reported previously in multiple individuals and families affected with breast and ovarian cancer (Farooq et al., 2011; Meindl, 2002). The p.Asn1355LysfsTer10 variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Asparagine 1355, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Asn1355LysfsTer10. Loss-offunction variants in BRCA1 are known to be pathogenic (Borg et al., 2010). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000019243	SCV004212727	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159924	SCV004224872	pathogenic	not provided	2022-08-08	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159924	SCV004242817	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159924	SCV004563957	pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	The BRCA1 c.4065_4068delTCAA; p.Asn1355LysfsTer10 variant (rs80357508), also known as 4184_4187del4, is reported in the literature in multiple individuals and families with breast and ovarian cancer (Evans 2004, Farooq 2011, Friedman 1994, George 2013, Leongamornlert 2014, Li 2019, Meindl 2002, Neuhausen 1996, Zhang 2011). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 17674), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 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: Evans DG et al. Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families. J Med Genet. 2004 Feb;41(2):e21. PMID: 14757871. Farooq A et al. Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report. J Oncol. 2011;2011:632870. PMID: 21559243. Friedman LS et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399-404. PMID: 7894493. George J et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013 Jul 1;19(13):3474-84. PMID: 23633455. Leongamornlert D et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer. 2014 Mar 18;110(6):1663-72. PMID: 24556621. 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. Meindl A et al. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002 Feb 1;97(4):472-80. PMID: 11802209. Neuhausen SL et al. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet. 1996 Feb;58(2):271-80. PMID: 8571953. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048431	SCV004848176	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.Asn1355LysfsX10 variant in BRCA1 has been reported in >100 individuals with BRCA1-associated cancers (Friedman 1994 PMID:7894493, Zhang 2011 PMID:21324516, George 2013 PMID:23633455, Cao 2013 PMID:23175448, Cunningham 2014 PMID:24504028, Leongamornlert 2014 PMID:24556621, Rashid 2016 PMID:27553291, Sun 2017 PMID:28724667, Maxwell 2017 PMID:28831036, Hirasawa 2017 PMID:29348823, Li 2018 PMID:30078507, Singh 2018 PMID:29470806, Wen 2018 PMID:28993434, Li 2019 PMID:29752822, Breast Information Core Database (BIC): https://research.nhgri.nih.gov/bic/). It has also been identified in 0.004% (3/68040) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1355 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 17674). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000159924	SCV005198184	pathogenic	not provided	2023-09-22	criteria provided, single submitter	clinical testing
OMIM	RCV000019243	SCV000039531	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019243	SCV000053742	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019243	SCV000144954	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	RCV000048431	SCV000587372	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353670	SCV000591484	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asn1355LysfsX10 variant was identified in 7 of 7698 proband chromosomes (frequency: 0.0009) from individuals or families with breast, ovarian, and prostate cancer and was not identified in 3994 control chromosomes from healthy individuals (Leongamornlert 2014, George 2013, Cao 2013, Alvarez 2017, Hoberg-Vetti 2016, Rashid 2016, Thompson 2016). The variant was also identified in the following databases: dbSNP (ID: rs80357508) as “With Pathogenic allele”, ClinVar (18x pathogenic including review by expert panel ENIGMA, 1x likely pathogenic), LOVD 3.0 (23x), UMD-LSDB (88x, causal), and the BIC Database (144x pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang University Database. In addition, the variant was identified by our laboratory in two individuals with breast cancer. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (Feb 27, 2017). The c.4065_4068delTCAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1355 and leads to a premature stop codon at position 1364. 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 hereditary 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000019243	SCV000733615	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735453	SCV000863590	pathogenic	Breast and/or ovarian cancer	2010-07-08	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV000735453	SCV001451833	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000159924	SCV001906313	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000476410	SCV002520862	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000019243	SCV002588804	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000019243	SCV003927180	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A known pathogenic mutation was detected in the BRCA1 gene in this specimen. This sequence change creates a premature translational stop signal (p.Asn1355Lysfs*10) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 14757871, 8571953, 11802209, 21559243). This variant is also known as 4184del4 in the literature. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.