Table 3.

Strategies used to clarify the clinical role of VUS.

Direct Genetic Evidence	Indirect Genetic Evidence
Co-segregation with the disease	In silico predictions based on the position and nature of the amminoacid change
Co-occurrence with known pathogenic mutations	In vitro functional assays
Comparison of allele frequency in cases and controls	Biochemical assays for protein characterization
	LOH and methylation analysis in vivo