Editor—Two breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified.1-3 Combined, these large and complex genes have over 800 reported genetic variants. More than 50 variants occurring within the introns of these genes are known. The clinical significance of these intronic variants, which could potentially impact RNA splicing, is largely undetermined.4-7

A variant within intron 20 of BRCA1 occurs through the duplication of 12 base pairs (bp) (GTATTCCACTCC) 48 bp from the donor junction. This variant has been observed in patients from cancer families.8-10 Furthermore, biochemical analysis showed the loss of contribution by one chromosome to the normal RNA in a breast cancer patient with IVS20ins12.11 This was shown by sequencing cDNA which showed the loss of a heterozygous base at the silent polymorphism at codon 1436 (serine TCT or TCC). These authors concluded that IVS20ins12 could represent a clinically significant regulatory mutation, although this variant was also present in a control specimen. More recently, IVS20ins12 was reported in four controls (with varying family histories of cancer, but otherwise healthy) and one early onset breast/ovarian cancer patient in a Polish BRCA1 study.12 No aberrant splicing products were detected in these samples, but mRNA abundance and possible loss of transcript have not been assayed. These authors concluded that the issue merits a more extensive study.

Here, a patient diagnosed with breast cancer at the age of 40 and with …