BRCA1 NM_007294.3:c.5407-10G>A, ?

The c.5407-10G>A intronic variant results from a G to A substitution 10 nucleotides upstream from coding exon 21 in the BRCA1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA analyses have demonstrated this variant to result in an 8 nucleotide insertion resulting in frameshift and premature truncation of the final 27 amino acids in a region that is critical for protein function (Ambry internal data; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Bozsik A et al. Cancer Res Treat, 2022 Oct;54:970-984). One functional study found that this nucleotide substitution has intermediate function in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The BRCA1 c.5407-10G>A variant has been reported in the published literature in individuals with ovarian cancer (PMID: 39733403 (2024)) and breast cancer (PMID: 35167739 (2022)). Assessment of experimental evidence suggests this variant results in abnormal RNA splicing and results in premature termination of the protein (PMID: 35167739 (2022), 31143303 (2019)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic.

This sequence change falls in intron 21 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs273901767, gnomAD 0.0009%). This variant has been observed in individual(s) with breast cancer (PMID: 34981296, 35167739). ClinVar contains an entry for this variant (Variation ID: 96950). Studies have shown that this variant results in activation of a cryptic splice site and introduces a new termination codon (PMID: 31143303, 35167739). However the mRNA is not expected to undergo nonsense-mediated decay. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.