Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000527927 | SCV000635783 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2017-05-26 | criteria provided, single submitter | clinical testing | This variant, c.122_134delinsT, is a complex sequence change that results in the deletion of the last 5 amino acid residues of exon 3 BRCA1 protein and the insertion of 1 residue  (p.His41_Lys45delinsGln). This variant also affects the last nucleotide, which is part of the consensus splice site for this exon. 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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. However, the deletion removes essential amino acids  from the highly conserved residues of the N-terminal BRCA1 RING domain (PMID: 12732733, 22843421). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Different missense substitution at these codons (p.Cys44Phe, p.Cys44Tyr, p.His41Arg) have been determined to be pathogenic (PMID: 23633455, 18159056, 25777348, 16267036 19543972, 27083775, 21922593, 25823446, 15168169, 24489791). This suggests that these residues are critical for BRCA1 protein function and that deletion of these amino acids may also be pathogenic. In summary, this variant is a novel deletion/insertion that removes highly conserved residues of the BRCA1 RING domain that have been determined to be pathogenic. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |