ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4065_4068del (p.Asn1355fs) (rs80357508)

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Total submissions: 24
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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 2019-01-09 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 2018-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000159924 SCV000210049 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA1 is denoted c.4065_4068delTCAA at the cDNA level and p.Asn1355LysfsX10 (N1355KfsX10) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATAA[delTCAA]GAAG. The deletion causes a frameshift, which changes an Asparagine to a Lysine at codon 1355, and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as BRCA1 4184del4 or 4184_4187delTCAA using alternate nomenclature, has been reported in association with hereditary breast cancer and in multiple individuals with breast, ovarian, or prostate cancer (Friedman 1994, Neuhausen 1996, Liede 2002, Meindl 2002, Farooq 2011, Couch 2015, Bu 2016, Chan 2018). We consider this variant to be pathogenic.
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 2015-03-02 criteria provided, single submitter clinical testing
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048431 SCV000591484 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Color RCV000131887 SCV000683147 pathogenic Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
DNA and Cytogenetics Diagnostics Unit,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
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
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

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