Genetic testing revealed a huge number of ATM (ataxia-telangiectasia mutated) variants of uncertain significance (VUS), despite the fact that germline pathogenic ATM (ataxia-telangiectasia mutated) variations were linked to an increased risk of several malignancies. 

For a study, germline ATM variations were examined by researchers in a real-world cohort of 336 individuals with chronic lymphocytic leukemia (CLL) and public cancer whole-exome/genome-sequencing datasets (445 CLL, 75 mantle cell lymphoma, 216 metastatic breast cancer, 140 lung cancer patients). With a frequency of up to 8% depending on the kind of cancer, they discovered that two-thirds of uncommon germline ATM variations were pathogenic (18%-50%) or VUS-predicted harmful (50%-82%), and one-third are benign. Patients who have heterozygous, predominantly missense pathogenic variations that are both harmful and predicted by VUS are more likely to develop deletion (del)11q than those without these variants, comparable to patients with somatic ATM mutations. 

A functional assessment of ATM activity in primary CLL cells demonstrated that concurrent del(11q) caused a total loss of ATM activity while VUS-predicted pathogenic ATM variants only partially impair ATM activity. Similar to somatic ATM or TP53 disruptions, the uncommon germline variations were linked to decreased progression-free survival in CLL on new medicines.

The findings demonstrated the necessity of establishing the pathogenicity of VUS in clinically significant genes like ATM.

Reference: onlinelibrary.wiley.com/doi/10.1111/bjh.18419