ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.*92dup (rs397507254)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223553 SCV000273171 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Structural Evidence,Other data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000297121 SCV000329664 likely pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA1 is denoted c.5578dupC at the cDNA level and p.His1860ProfsX20 (H1860PfsX20) at the protein level. Using alternate nomenclature this variant would be defined as BRCA1 5697dupC. The normal sequence, with the base that is duplicated in brackets, is TCCCC[dupC]ACAG. The duplication causes a frameshift, which changes a Histidine to a Proline at codon 1860, and creates a premature stop codon at position 20 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, it is likely to be significant since the last 4 correct amino acids are replaced by 19 incorrect ones, impacting a region known to interact with BRCA2 and multiple other proteins (Paul 2014). This variant was incidentally observed in an individual who underwent exome sequencing and was classified as expected pathogenic; of note, this individual's personal and family history of cancer were not reported (Lawrence 2014). Based on the currently available information, we consider BRCA1 c.5578dupC to be a likely pathogenic variant.
Invitae RCV000470909 SCV000549376 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-10-06 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 23 of the BRCA1 mRNA (c.5578dupC), causing a frameshift at codon 1860. This is expected to delete the last 4 amino acids of the BRCA1 protein and replace them with 19 amino acid residues, creating a new downstream translational stop signal that extends the length of the protein (p.His1860Profs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to result in an altered C-terminal end of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37683). The BRCT domain (residues 1646-1859) of BRCA1 is important for its DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403) and the frameshift caused by this variant directly affects only the amino acids that are downstream of this domain. While this variant is expected to cause a structural change at the C-terminal end of the protein, functional studies have not been performed to test whether or not it affects protein function. In summary, this is a rare frameshift variant with uncertain impact on protein function. In the absence of genetic and/or functional data, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000031264 SCV000053869 likely pathogenic Breast-ovarian cancer, familial 1 2006-07-25 no assertion criteria provided clinical testing

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