Table 2 Types of reinterpretation illustrated by fictional cases^a

Reactive reinterpretation

 The laboratory conducts reinterpretation of previously identified variants due to an external trigger. This can be a) a request from patient or clinician or b) identifying a previously classified variant in a new patient

 Case a. Reactive reinterpretation upon request:

 Ms. P’s 10 year old child, A, has learning difficulties. A is referred to Dr. F, a clinical geneticist, and a genetic test is performed, identifying a variant of uncertain significance (VUS/class 3) in FOXP2. Dr. F discusses this result with Ms. P, explaining that a genetic variant has been identified that could possibly be the cause for A’s learning difficulties, but could equally likely play no part. Dr. F recommends that Ms. P return to the clinic in a few years to enquire whether new information is available. Ms. P contacts Dr. F two years after the initial results, who in turn contacts the laboratory to inform about the current state of affairs regarding the FOXP2 VUS. The laboratory reinterprets the variant and informs Dr. F that the variant can now be reclassified as class 1 benign and therefore non-causal for A’s symptoms.

 Case b. Reactive reinterpretation upon identification of variant in new patient:

 Mr. C is diagnosed with colorectal cancer and is referred for genetic testing. A likely pathogenic variant (LP/class 4) in MSH6 is identified. Three years later a different patient, Ms. L, unrelated to Mr. C, is referred to the clinic due to colorectal cancer. A genetic test is performed and the same MSH6 variant is identified. Review of the evidence now suggests it is a pathogenic (class 5) variant and the classification in Mr. C’s case is also changed to pathogenic. A new report informing of this change is issued to Mr C’s clinician.

Active reinterpretation

 The laboratory initiates reinterpretation of previously identified variants, without an external trigger

 Case c. Active reinterpretation:

 A molecular genetics laboratory decides to biannually reinterpret all variants that are classified as VUS in their database. When new evidence is sufficient, these variants are reclassified and their new classification is registered in the laboratory’s database. Clinicians whose patients have been identified to carry these variants are informed of the reclassifications. All patients whose genetic testing is conducted through this laboratory are informed of this policy at their clinical consultations.