BRCA1 NM_007294.4:c.442-22_442-13del, ?

The c.442-22_442-13del10 intronic pathogenic mutation, located in intron 5 of the BRCA1 gene, results from a deletion of 10 nucleotides within intron 5 of the BRCA1 gene. This alteration is identified in numerous individuals with a clinical history of breast and/or ovarian cancer and it segregates with disease in multiple families (Lin PH et al. Oncotarget, 2016 Feb;7:8310-20; Wong ES et al. PLoS One, 2015 Jul;10:e0134408; Ang P et al. Cancer Epidemiol Biomarkers Prev, 2007 Nov;16:2276-84; Li SS et al. Hum Genet, 1999 Mar;104:201-4). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. This alteration leads to the use of a cryptic acceptor site within intron 5 leading to a partial inclusion of this intron and a protein with a premature termination codon (Ambry internal data; Li SS et al. Hum Genet, 1999 Mar;104:201-4; Ang P et al. Cancer Epidemiol Biomarkers Prev, 2007 Nov;16:2276-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This variant causes a 10 nucleotide deletion near the splice acceptor site in intron 6 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies on carrier-derived RNA has shown an out-of-frame splicing associated with variant (PMID: 10323242, 18006916, 32745242). Moreover, cellular characterization on ex vivo cells derived from carriers showed sensitivity to PARP inhibitor and other cellular features consistent with compromised BRCA1 function in the normal cellular response to DNA damage and DNA replication blockage (32745242). This variant has been reported in over 10 individuals affected with breast and/or ovarian cancer (PMID: 10323242, 18006916, 26824983, 32745242, 34503154), and a haplotype analysis suggests that this variant may be founder mutation among Han Chinese (PMID: 32745242). This variant also has been reported to segregate with breast and ovarian cancers in at least five carrier families (PMID: 10323242, 32745242). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change falls in intron 6 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 may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10323242, 18006916, 26221963, 26824983; internal data). It is commonly reported in individuals of Asian ancestry (PMID: 10323242, 18006916, 26221963, 26824983; internal data). This variant is also known as IVS7-15del10, IVS7-22del10, and g.41251910_41251919 delGTAAAGAACA. ClinVar contains an entry for this variant (Variation ID: 246362). Studies have shown that this variant results in insertion of 59 bp in intron 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10323242, 18006916). For these reasons, this variant has been classified as Pathogenic.