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.