Table 2

Five strengths of variant of uncertain significance, annotated by potential evidence combinations, posterior probability of pathogenicity, ‘exponent sum’ and UK-ACGS Best Practice Guidelines for Variant Classification in Rare Disease descriptor4

Exponent score for evidence elementsExponent sumOverall (posterior) probability of pathogenicity (%)UK-ACGS descriptor
Towards pathogenicity: 8 (very strong),
4 (strong), 2 (moderate), 1 (supporting)
towards benignity: −4 (strong), −1 (supporting)
4+150.812 (81.2)Hot VUS
2+2+1
2+1+1+1
1+1+1+1+1
440.675 (67.5)Warm VUS
2+2
2+1+1
1+1+1+1
2+130.500 (50.0)Tepid VUS
1+1+1
220.325 (32.5)Cool VUS
1+1
110.188 (18.8)Ice-cold VUS
  • UK-ACGS, UK Association for Clinical Genomic Science; VUS, variant of uncertain significance.