ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4065_4068del (p.Asn1355fs) (rs80357508)

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Total submissions: 31
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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 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 and ovarian cancer syndrome 2020-10-30 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. This variant is present in population databases (rs80357508, ExAC 0.006%). 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. ClinVar contains an entry for this variant (Variation ID: 17674). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131887 SCV000186942 pathogenic Hereditary cancer-predisposing syndrome 2019-03-26 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 and ovarian cancer syndrome 2017-02-01 criteria provided, single submitter clinical testing
Counsyl RCV000019243 SCV000220878 likely pathogenic Breast-ovarian cancer, familial 1 2014-11-14 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159924 SCV000296305 pathogenic not provided 2019-03-20 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
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 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 1 2015-11-20 criteria provided, single submitter clinical testing
Genologica Medica RCV000019243 SCV000577930 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000019243 SCV000584013 pathogenic Breast-ovarian cancer, familial 1 2017-07-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131887 SCV000683147 pathogenic Hereditary cancer-predisposing syndrome 2021-02-14 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 variant has been reported in numerous individuals affected with breast and ovarian cancer (e.g., PMID: 23633455, 23683081, 27553291, 28724667, 28993434, 29339979, 29470806, 29752822, 30078507, 30825404) and familial 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 and 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 1 2017-05-31 criteria provided, single submitter clinical testing
Mendelics RCV000048431 SCV000839242 pathogenic Hereditary breast and 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 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 Karolinska University Hospital,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 1 2020-04-02 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659712 SCV001878623 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
OMIM RCV000019243 SCV000039531 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019243 SCV000053742 pathogenic Breast-ovarian cancer, familial 1 2013-03-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019243 SCV000144954 pathogenic Breast-ovarian cancer, familial 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 and 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 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

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