We have a robust system in place for identifying which variants require confirmation. Our confirmation rules for SNVs and indels (single base changes and small insertions and deletions) are as follows:
-
We confirm a variant if:
-
It is confidently called by our computational pipeline and has been interpreted as likely pathogenic or pathogenic (disease causing). The only exceptions are variants that have already been whitelisted (see below).
-
It is not called confidently by our computational pipeline and it has been interpreted as pathogenic, likely pathogenic, or a variant of uncertain significance (VUS).
-
We do not confirm a variant if:
-
It is confidently called and interpreted as a variant of uncertain significance.
-
It is on our confirmation whitelist. To be on the whitelist, a variant must have been confidently called and confirmed with an orthogonal method 10 or more times in our lab. The creation of a whitelist follows the recommendation of the New York State Clinical Laboratory Evaluation Program, which proposed the concept. These variants tend to be common pathogenic variants in the population that have been seen and correctly called so many times that we are confident that no confirmation is needed. For a variant to attain whitelist status, it requires a large number of patients be tested and the variant to be detected and confirmed numerous times. As of October 2016, there are only ~70 variants on the list.