RRML - Pathogenic intronic and deleterious benign variants: two extremes in cancer predisposition molecular diagnosis
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Dr. Adrian Man

   
 
Nr. 20(4)/2012
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Pathogenic intronic and deleterious benign variants: two extremes in cancer predisposition molecular diagnosis

Lucian Negură, Anca Negură, Andrei Coneac, Ioana Berindan Neagoe, Doina Azoicăi, Alexandru Irimie


Abstract:

Molecular diagnosis in cancer predisposition is today current practice in Western Europe, which allows oncogenetic follow-up of patients and their families. Diagnosis is mainly targeting BRCA, MMR and APC genes, involved in hereditary breast and ovarian cancer syndrome (HBOC), hereditary non-polyposic colorectal cancer or Lynch syndrome (HNPCC), and familial adenomatous polyposis (FAP) respectively. Carriers of deleterious mutations in any of these genes are at significantly higher risk of developing cancer than general population. Thousands of BRCA sequence variations have already been reported, but not all variants can be considered pathological. Deleterious mutations and common non-pathogenic single nucleotide polymorphisms are usually detected, but almost a half of the observed variations are of uncertain clinical significance. In-silico analysis including sequence alignments, tolerance prediction and splicing analysis is therefore essential for understanding possible effects on protein function and pathogenicity. While completely sequencing BRCA1 and BRCA2 genes in routine molecular diagnosis, we found several unclassified variants which easily can blur analysis, either being false-positive or false-negative. We show here that extreme examples such as pathogenic intronic and deleterious benign variants represent real challenges in molecular diagnosis. Good experience, a lot of attention and responsibility are essential in order to avoid errors.

Keywords: molecular diagnosis,unclassified variants,in-silico analysis,false positives,false negatives.

 
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How to cite
Negură L, Negură A, Coneac A, Berindan Neagoe I, Azoicăi D, Irimie A. Pathogenic intronic and deleterious benign variants: two extremes in cancer predisposition molecular diagnosis. Rev Romana Med Lab. 2012;20(4):317-26