ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5521del (p.Ser1841fs) (rs80357721)

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Total submissions: 5
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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) RCV000112693 SCV000300276 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 RCV000049034 SCV000077047 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-14 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide in exon 23 of the BRCA1 mRNA (c.5521delA), causing a frameshift at codon 1841. This creates a premature translational stop signal in the last exon of the BRCA1 mRNA (p.Ser1841Valfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated protein by eliminating 22 amino acid residues from the full-length BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 9544766, 16835750, 21614564, 27393621). This variant is also known as 5640delA in the literature. ClinVar contains an entry for this variant (Variation ID: 55612). This truncation is expected to partially remove the C-terminal BRCT domain of BRCA1 protein, which is important for DNA repair activity (PMID: 14576433, 15133503). A different deleterious variant p.Tyr1853* located downstream of this variant has been shown to disrupt BRCA1 protein function (PMID: 8942979, 20681793, 10811118, 11256609, 17308087), suggesting that although this particular variant may not result in nonsense mediated decay, it is expected to affect BRCA1 protein function. For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112693 SCV000326351 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564883 SCV000661000 pathogenic Hereditary cancer-predisposing syndrome 2016-02-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA1) RCV000112693 SCV000145565 pathogenic Breast-ovarian cancer, familial 1 1999-04-06 no assertion criteria provided clinical testing

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