ClinVar

Description

The BRCA1 c.5468-?_5592+?del deletion variant (chr17.GRCh37/hg19.g.41197693-?_41197817+?del) results in a deletion of exon 24, although the precise breakpoints of this deletion were not determined, nor were the effects of this variant on the resulting mRNA or protein product determined. The variant was identified in 19 of 7164 proband chromosomes (frequency: 0.003) from selected and unselected (familial or without family history) Greek and German individuals or families with breast and ovarian cancer (Engert 2008, Armaou 2007, Armaou 2009, Stavropoulou 2013). In two studies, two deletions were found to encompass the polyA tail region and 3’ untranslated region (UTR) of the gene; however, the exact breakpoints were determined and they differed (Engert 2008, Armaou 2007). RNA analysis from both studies showed a loss of transcript, suggesting that the deletion of the polyA tail region and 3’UTR may result in nonsense-meditated decay of the variant RNA transcript. Armaou et al (2009) also describe that 10% of Greek patients who develop early onset breast cancer (<40 yrs) carry 1 of 4 common BRCA1 mutations which included the deletion of exon 24. The variant was not identified in dbSNP, Clinvitae database, LOVD-IARC database, ARUP Laboratories BRCA Mutations Database,COSMIC, the ClinVar database), GeneInsight COGR database, the BIC database, and UMD, Fanconi Anemia Mutation Database (LOVD). The variant was also identified by our laboratory in 1 additional individual with ovarian cancer. This alteration is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.