ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5558dup (p.Tyr1853Ter) (rs80357629)

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Total submissions: 11
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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) RCV000074357 SCV000300281 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000049050 SCV000077063 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the BRCA1 mRNA at codon 1853 (p.Tyr1853*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 11 amino acids of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with breast and/or ovarian cancer  (PMID: 24504028, 20104584) and has been reported to segregate with breast cancer in a single family (PMID: 7894493). This variant is also known as (c.5677insA, Y1853_L1854delinsX) in the literature. ClinVar contains an entry for this variant (Variation ID: 55628). Experimental studies have shown that this nonsense change induces a delocalization of BRCA1 in the cytoplasm, impairs the formation of nuclear foci, reduces transcriptional activation, and shows a pronounced enlargement of the unfolded chromatin structure (PMID: 21922593, 10811118, 11739404, 12400015). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000163976 SCV000214576 pathogenic Hereditary cancer-predisposing syndrome 2017-10-09 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 RCV000265181 SCV000329130 pathogenic not provided 2017-08-11 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA1 c.5558dupA at the cDNA level and p.Tyr1853Ter (Y1853X) at the protein level. The normal sequence, with the base that is duplicated in braces, is ACCT[A]CCTG. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon, and is predicted to cause loss of normal protein function through protein truncation, causing the loss of the last 11 amino acids. BRCA1 c.5558dupA, previously reported as BRCA1 c.5677dupA, has been reported in association with breast and/or ovarian cancer and was shown to segregate with disease in at least one family (Friedman 1994, Borg 2010). Functional assays including those measuring transcription activity and proteolytic stability all confirm the pathogenic nature of this variant (Monteiro 1996, Williams 2010). In addition, this nonsense variant has been reported in public databases (LOVD and BIC), albeit due to different amino acid changes (c.5558C>A and c.5559C>A). It was shown to be functionally abnormal, decreasing formation in the nucleus, showing lack of transcription, and failing to suppress VEGF activity (Hayes 2000, Kawai 2002, Millot 2011). Based on currently available evidence, we consider this variant to be pathogenic.
Counsyl RCV000074357 SCV000488476 pathogenic Breast-ovarian cancer, familial 1 2016-04-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000265181 SCV000888951 pathogenic not provided 2017-09-07 criteria provided, single submitter clinical testing
Color RCV000163976 SCV000904687 pathogenic Hereditary cancer-predisposing syndrome 2015-12-10 criteria provided, single submitter clinical testing
OMIM RCV000074357 SCV000039536 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000074357 SCV000053867 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000074357 SCV000145577 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 RCV000049050 SCV000587522 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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