Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001024278 | SCV001186263 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-30 | criteria provided, single submitter | clinical testing | The c.5563delAinsGGATCC variant, located in coding exon 22 of the BRCA1 gene, results from the deletion of one nucleotide and insertion of 6 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.I1855Gfs*69). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BRCA1, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 58 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. One functional study found that this alteration impaired BRCA1 transcriptional activation activity (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001241613 | SCV001414641 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2024-04-30 | criteria provided, single submitter | clinical testing | This sequence change results in a frameshift in the BRCA1 gene (p.Ile1855Glyfs*69). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the BRCA1 protein and extend the protein by 68 additional amino acid residues. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. The frameshift caused by this variant affects the C-terminal end of the BRCA1 protein, partially including the BRCT domain (residues 1646-1859), which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While a protein structural change is likely expected, functional studies have not been done to test whether or not this variant affects protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |