Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000817388 | SCV000957943 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-08-14 | criteria provided, single submitter | clinical testing | This sequence change results in a frameshift in the BRCA1 gene (p.Asp1840Argfs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the BRCA1 protein and extend the protein by 15 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 660234). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 21922593; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000817388 | SCV002074535 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2023-12-11 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.5517_5518insC (p.Asp1840ArgfsX40) causes a frameshift which results in an extension of the protein. This variant is located in the last exon and is unlikely to result in nonsense mediated decay, but is predicted to replace the last 24 amino acids, creating a new downstream translational stop signal in the last exon and lengthening the C-terminus of the protein. The variant was absent in 251360 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5517_5518insC in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, this frameshift is located in C-terminus of the protein and affects a part of BRCT domain (IPR001357, 1756-1855), which is important for DNA repair activity. Additionally, other downstream deleterious variants were classified as likely pathogenic/pathogenic in our laboratory and ClinVar database. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |