ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2346dup (p.Ile783fs) (rs886040027)

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Total submissions: 6
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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) RCV000257107 SCV000323441 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 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 RCV000257107 SCV000325329 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000465165 SCV000549404 pathogenic Hereditary breast and ovarian cancer syndrome 2016-11-26 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 10 of the BRCA1 mRNA (c.2346dupT), causing a frameshift at codon 783. This creates a premature translational stop signal (p.Ile783Tyrfs*7) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507973 SCV000600284 likely pathogenic not provided 2016-08-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509736 SCV000607935 pathogenic Hereditary cancer-predisposing syndrome 2016-10-03 criteria provided, single submitter clinical testing The c.2346dupT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of T at nucleotide position 2346, causing a translational frameshift with a predicted alternate stop codon (p.S782Sfs*8). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000465165 SCV000698941 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2346dupT (p.Ile783Tyrfs) 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.2389G>T (p.Glu797X), c.2411_2412delAG (p.Gln804fs), and c.2433delC (p.Lys812fs)). Mutation Taster predicts a damaging outcome for this variant. This variant is absent in 121364 control chromosomes from the ExAC database, a large control database. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.

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