Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm

open access (Myriad Genetics)

Conclusions

We have developed and implemented a HWA to aid in the classification of VUSs in genes associated with Lynch syndrome. The work presented here demonstrates that this HWA is able to classify MLH1, MSH2, and MSH6 VUSs as either benign or pathogenic with high accuracy.

 It is extremely difficult to identify low penetrance variants with current variant classification methods, and the HWA shares this limitation. Our previously described experience with known hypomorphic variants in BRCA1 and BRCA2 has shown that, even after observations in large numbers of probands, these lower penetrance variants will not produce a HWS falling within the defined threshold for either the negative or positive control ECDF.⁷ Variants behaving in this fashion are clearly suspect for lower penetrance, but we cannot rule out the possibility that there are some LS gene variants called as benign with the HWA which are associated with low penetrance for one or more Lynch cancers. It is arguable as to whether this type of variant should be regarded as pathogenic for LS, since current medical management guidelines for LS would probably not apply.