Copy number variants
The whole CHEK2 deletion was weighted as PVS1 Stand-alone, as
proposed for full gene deletions of known haploinsufficiency (Abou
Tayoun et al., 2018), being classified P by all frameworks. Deletion of
exons 3 and 4 occurs in-frame and produces the loss of the entire
critical FHA domain, for this reason PVS1 was weighted. Together with
PM2_supporting it would be a VUS with traditional ACMG combination
rules but would be classified as LP following ClinGen-TP53 as
well as using Tavtigian’s calculations. Deletion of exon 2 removes the
first methionine and deletes 45 amino acids of the FHA domain, essential
for CHK2 protein function, therefore, PVS1 was applied as “strong”.
Together with PM2_supporting, it did not reach LP/P classification in
any framework.