ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5474_5481del (p.Gly1825fs) (rs730881441)

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Total submissions: 4
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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) RCV000241142 SCV000300265 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000159845 SCV000209887 pathogenic not provided 2014-04-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5474_5481delGGCAGATG at the cDNA level and p.Gly1825ValfsX2 (G1825VfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATTG[GGCAGATG]TGTGA. The deletion causes a frameshift, which changes a Glycine to a Valine at codon 1825, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. BRCA1 5474_5481delGGCAGATG, previously reported as 5593del8 using alternate nomenclature, has been observed in association with breast and/or ovarian cancer (Judkins 2005). We therefore consider this to be a pathogenic variant.
Ambry Genetics RCV000163754 SCV000214331 pathogenic Hereditary cancer-predisposing syndrome 2018-03-03 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)
Invitae RCV000804331 SCV000944235 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Gly1825Valfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acids of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182075). 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 truncation (p.Tyr1853*) that lies downstream of this variant has been determined to be pathogenic (PMID: 24504028, 20104584, 7894493, 21922593, 10811118, 11739404, 12400015). This suggests that deletion of this region of the BRCA1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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