Description
This variant is denoted BRCA1 c.593+4A>G or IVS8+4A>G and consists of an A>G nucleotide substitution at the +4 position of intron 8 of the BRCA1 gene. Multiple in silico models predict this variant to weaken the nearby natural donor site, and to possibly cause abnormal gene splicing. An in vitro splicing assay found that this variant results in deletion of exon 9; however, there is suggestion that deletion of exon 9 is a natural isoform in some tissues (Whiley 2011). The variant, also published as BRCA1 712+4A>G using alternate nomenclature, was predicted by Lindor et al. (2012) to be neutral based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations. BRCA1 c.593+4A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is not conserved. Based on currently available information, it is unclear whether BRCA1 c.593+4A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
