Submissions for variant NM_007294.4(BRCA1):c.5558dup (p.Tyr1853Ter) (rs80357629)

Total submissions: 11

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	2019-12-27	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 observed 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	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	2020-01-15	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