ClinVar

Description

The p.Val211Ile variant has been previously reported in the literature in 8 of 64 proband chromosomes of individuals with hereditary breast and/or ovarian cancer. However, no control chromosomes were evaluated to establish the prevalence of the variant in the general population (Colombo 2009, Pensabene 2009, Lowery 2011, Gaildrat 2012, Diez 2009). The variant occurs in the last base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Indeed, functional studies have shown that the variant altered the natural splice sites leading to exon skipping due to modification of the sequence of the 5' splice site (Pensabene 2009, Gaildrat 2012). The variant has also been reported twice in the UMD database as a variant of unknown significance, and 8 times in the BIC database as a clinically significant variant. In both the cases reported in the UMD database, the variant was found to co-occur with the pathogenic BRCA2 variant (c.7008-2A>T). This other variant is also being reported as co-occurring in this individual. In summary, based on the above information, this variant is classified as pathogenic.