Letter to the Editor: CHEK2 I157T - Pluto Among Numerous Low-Risk Genetic Factors Requiring Discharge From a Range of Pathogenic Variants?

Abstract

ing, and even laboratory genetics. With respect to CHEK2 variant carriers, NCCN Guidelines state that "The risks for most missense variants are unclear but for some pathogenic/likely pathogenic (P/LP) variants, such as Ile157Thr, the risk for breast cancer (BC) appears to be lower [than for frameshift pathogenic/likely pathogenic variants]. Management should be based on best estimates of cancer risk for the specific pathogenic/ likely pathogenic variant." This implies that CHEK2 p.Ile157Thr variant is considered by the NCCN Guidelines panel members to be classified as P/LP, and should be reported for risk management (contrary to variants classified as benign/likely benign [B/LB]).Without speculations on variant classification in accordance with American College of Medical Genetics and Genomics/Sherloc guidelines, 2,3 we may state that, first, this variant may be considered as a rare polymorphism (minor allele frequency [MAF] based on ExAC project 0.40%; in comparison: highest MAF across BRCA1/2 P/LP variants at 0.026% [ExAC] for BRCA2 p.Ser1982fs and the second highest MAF at 0.0067% [ExAC] for BRCA2 p.Cys61Gly, which are 16 times and 60 times higher than MAF for the CHEK2 p.Ile157Thr variant, respectively). Second, risk for BC associated with this variant appears to be low (as noted by current NCCN Guidelines, odds ratio [OR] for BC, 1.58; 95% CI, 1.42-1.75). 4 These put this variant in line with other rare polymorphisms, which, despite B/LB classification (as of majority of CLINVAR submissions), may confer increased risk for BC (though significantly lower, compared with P/LP variants of the same gene). For example, BRCA2

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2

“…Moreover, p.I157T, p.T476M, and p.S428F were associated with lower rates of non-BCs compared with WT. Classification of these variants is inconsistent, and in a previous study of bioinformaticists and clinical geneticists, Agaoglu et al showed that the p.T476M alteration was classified as a variant of unknown significance, likely pathogenic or pathogenic by different interpreters. Although BC frequency with the p.I157T variant was not significantly different from WT, the frequency of bilateral BCs was (OR, 1.52; P < .001), indicating this variant may act in concert with other genetic modifiers influencing BC risk.…”

Untapped Potential of Poly(ADP-Ribose) Polymerase Inhibitors: Lessons Learned From the Real-World Clinical Homologous Recombination Repair Mutation Testing

“…Variants of uncertain significance, both somatic and germline, are referred to as VUS. CHEK2 variant p.Ile157Thr (rs17879961) was considered as non-deleterious and was not included in the final analysis [ 75 ].…”

Hereditary Breast Cancer in Romania—Molecular Particularities and Genetic Counseling Challenges in an Eastern European Country

“…Compared to other CHEK2 pathogenic variants, c.470T>C has an attenuated association with BC, was not associated with non-breast cancers [33,34], and is probably modulated by other genetic factors or non-genetic risk factors to increase BC risk. Along with hormone-related risk factors [35], it has been shown that a family history of BC correlates with higher risks for women with CHEK2 pathogenic variants [36][37][38]. Surprisingly, the common c.1100del CHEK2 variant was reported only in one patient.…”