Interpreting VUS

Question 1

What are the 5 classes of vus and what further testing of family members and surveillance is recommended?

Answer 1

5: definitely pathogenic - test relatives and high surveillance
4: likely pathogenic- same as 5
3: uncertain- not use as predictive test in rels, surveillance based on FH
2: likely not pathogenic or little clinical sig- not predictive text in relatives and treat as no mutation detected
1: not pathogenic and no clinical sig- same as 2

Question 2

What criteria should be used to investigate a vus?

Answer 2

Comprehensive lit search
Mutation/snap databases- inc in house, check external curated
Test normal controls
Co-occurrence with known deleterious mutation
Co-segregation with family
De novo?
In silico predictions
Rna studies
Functional studies