Recent analysis published in Scientific Reports has concluded that c.9227G>T is a BRCA2 pathogenic variant.
Variants of uncertain significance
The clinical interpretation of sequence variants from next generation sequencing (NGS) approaches is a challenge. In particular, variants of uncertain significance (VUSs) pose a huge dilemma as they are not clinically actionable. As a result, efforts are currently underway to try and reclassify these variants, such as work done by the international consortium Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA).
BRCA1/2 pathogenic variants account for about one fourth of all breast and ovarian cancer families. However, VUSs are the results of a smaller fraction of all tests (2-20%). Clinicians cannot use these variants for the identification of predisposed family members. Therefore, healthy individuals from high risk families can only be managed based on specific family history.
The identification of pathogenic variants allows for early detection and prevention strategies in healthy carriers. It also allows for targeted treatments in patients affected with BRCA-associated tumours.
Segregation analysis
In this study, during molecular analysis of BRCA1/2 genes in over 6,000 breast and/or ovarian cancer patients, researchers identified 15 families carrying the BRCA2 c.9227G>T variant. International databases rarely report the BRCA2 c.9227G>T p.(Gly3076Val) variant; yet it frequently recurs in families from Northeast Italy. This variant results in a substitution of the evolutionary invariant glycine 3076 with a valine in the DNA binding domain of the BRCA2 protein. Therefore, this infers a high probability of pathogenicity.
Most of the families carrying this variant showed typical BRCA2 tumour spectra. They presented with frequent bilateral breast tumours, early age of onset and presence of ovarian cancer. The researchers identified no other pathogenic variants or other VUSs in these families. Additionally, researchers found that the variant co-segregated in families with breast and ovarian cancer.
These results, combined with in silico predictions and functional impairment of DNA double strand break repair, provide definitive evidence for pathogenicity. This allows for reclassification of the variant to class 5 – definitely pathogenic (based on the ACMG/AMP guidelines).
The BRCA2 c.9227G>T variant can now be used in families to identify predisposed family members and guide in preventative and/or early detection strategies. Moreover, patients carrying the variant can benefit from targeted treatments such as PARP-inhibitors.
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