Lynch syndrome is an autosomal dominant cancer syndrome, predisposing to colorectal and endometrial cancer predominantly, caused by alterations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. MMR gene truncating variants that severely affect gene function can be identified in about half the families with suspected Lynch syndrome. However, more than 15 % of Lynch syndrome families present with MMR gene sequence variants of uncertain clinical significance (VUS). It can sometimes be difficult to predict whether these amino acid substitution and splice site region MMR gene variants are likely to be disease-associated simply by looking at the position and nature of the sequence change. Such variants present a challenge in the clinical setting for genetic counselling, and thorough evaluation of their clinical significance has direct clinical outcome for families concerned. We are testing the functional consequences of a panel of UVs in vitro, and comparing the use a combination of bioinformatics prediction tools, laboratory assays, and statistical models incorporating clinical information, ls to predict variant pathogenicity.
(Michael Parsons, Dylan Glubb, Troy Dumenil)