Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000803273 | SCV000943136 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2022-05-27 | criteria provided, single submitter | clinical testing | This variant results in a copy number gain of the genomic region encompassing exon(s) 20-21 of the BRCA1 gene. While the exact position of this variant cannot be determined from the data, sub-genic copy number gains are generally in tandem (PMID: 25640679). This variant is predicted to be in-frame, and likely preserves the integrity of the reading frame. A similar copy number variant has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 24522996). This variant is also known as duplication of exons 21-22 in the literature. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. The C-terminal region of the BRCA1 protein contains two BRCT repeats (BRCT-N and BRCT-C), which are essential for BRCA1 protein function (PMID: 10811118, 8751436). Structural and functional analyses have shown that the tandem BRCT domains form a well-organized structure crucial for BRCA1 transcriptional activity (PMID: 20516115, 11573086, 15172985). This variant is expected to disrupt the BRCT-C repeat, which would likely destabilize the structure of the C-terminal region of the BRCA1 protein and disrupt BRCA1 transcriptional activity Experimental studies using targeted deletions of highly conserved amino acids (Y1853-I1855) located in the most C-terminal hydrophobic cluster of the BRCT-C repeat have shown that structural integrity of this hydrophobic cluster is essential for BRCA1 transcriptional activity (PMID: 10811118, 18992264). This observation suggests that structural disruption of the C-terminal region of the BRCT-C may affect BRCA1 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. |