Nonsense and frameshift variants
Only one patient was carrier of the recurrent CHEK2 c.1100delC
mutation, p.(Thr367Metfs*15) (1 out of 2,346, 0.04%). Given the great
amount of data related to CHEK2 c.1100delC, this variant meets
PS3 (well established functional studies) and PS4 (higher prevalence in
affected individuals versus controls), besides PVS1. However,
PS4 was assigned with moderate strength (PS4_moderate), since
OR>5.0 for a moderately penetrant gene cannot be achieved.
The combination of these rules classified this variant as pathogenic (P)
in any combination of rules framework, and since it is well-studied and
frequent in some populations, it was classified as established risk
allele (ERA) within the Senol-Cosar framework (Table 1 and Table S2).
c.1368dupA, p.(Glu457Argfs*33) variant meets PS3 and PM2_supporting,
being classified as P in all frameworks. c.715G>T,
p.(Glu239*) variant meets PM2, therefore was classified as likely
pathogenic (LP) using ACMG and ClinGen-TP53 frameworks. According
to Tavtigian’s Bayes model (Tavtigian et al., 2018), it gathers enough
evidence to be classified as P. Variants c.279G>A,
p.(Trp93*) and c.591delA, p.(Val198Phefs*7) were weighted
PM2_supporting. The sum of PVS1 and a supporting criterion is not
enough to classify a variant as LP/P using ACMG guidelines (S. Richards
et al., 2015). However, application of Bayesian modelling of this
combination of rules gives a posterior probability of 0.988, resulting
in its classification as LP according to Tavtigian’s (S. Richards et
al., 2015; Tavtigian et al., 2018) as well as following
ClinGen-TP53 modifications (ClinGen-TP53_Expert_Panel, 2019).