ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3342_3345del (p.Glu1114_Glu1115insTer) (rs397509058)

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Total submissions: 12
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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) RCV000077543 SCV000299927 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077543 SCV000325625 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077543 SCV000488951 pathogenic Breast-ovarian cancer, familial 1 2016-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000521138 SCV000617452 pathogenic not provided 2017-09-28 criteria provided, single submitter clinical testing This deletion of four nucleotides is denoted BRCA1 c.3342_3345delAGAA at the cDNA level and p.Glu1115Ter (E1115X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3461_3464delAGAA. The normal sequence, with the bases that are deleted in brackets, is ATGA[delAGAA]GTAG. The deletion creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.3342_3345delAGAA has been observed in at least two individuals with breast and/or ovarian cancer and has been described as a recurrent variant in southern China (Kwong 2009, Kwong 2012). This variant is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496369 SCV000699021 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3342_3345delAGAA (p.Glu1115X) 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. If a stable protein product is made, p.Glu1115X would lack the C-terminal BRCT domains, vital for BRCA1 function. Additionally, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3748G>T/p.Glu1250X, c.3904G>T/p.Glu1302X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in at least two clinically high-risk and/or ovarian cancer patients and was absent in 121128 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Health, Inc RCV000776478 SCV000912040 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000521138 SCV001133549 pathogenic not provided 2019-07-30 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 not found in general population data.
Ambry Genetics RCV000776478 SCV001181468 pathogenic Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing The c.3342_3345delAGAA pathogenic mutation (also known as p.E1115*), located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3342 to 3345. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been recognized in individuals of Chinese descent with breast and/or ovarian cancer (Kwong A et al. PLoS ONE. 2012 Sep;7(9); Karami F and Mehdipour P. Biomed. Res. Int. 2013 Nov;2013:928562). 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.
Invitae RCV000496369 SCV001585111 pathogenic Hereditary breast and ovarian cancer syndrome 2020-06-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1115*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 19353265, 16528604, 22970155). This variant is also known as c.3450del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 54850). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077543 SCV000109344 pathogenic Breast-ovarian cancer, familial 1 2012-12-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077543 SCV000144729 uncertain significance Breast-ovarian cancer, familial 1 2013-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496369 SCV000587303 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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