Clinical Significance of Ataxia-Telangiectasia Mutated Pathogenic Germline Variant

Abstract

Ataxia-telangiectasia mutated (ATM) encodes a serine/threonine protein kinase that coordinates the cellular response to DNA double-strand breaks.Biallelic pathogenic variants in ATM cause ataxia-telangiectasia, an autosomal recessive multisystem disorder characterized by progressive neurologic impairment, immunodeficiency, radiation sensitivity, and an increased risk of malignancy.In contrast, monoallelic pathogenic variants in ATM are associated with moderate, cancer type-specific susceptibility, particularly to female breast, pancreatic, and prostate cancers.Importantly, ATM should not be interpreted as a BRCA1/2-equivalent gene, as cancer risk varies according to variant type, cancer type, family history, and population background.Current evidence supports enhanced breast surveillance and selective pancreatic and prostate cancer screening for carriers of pathogenic ATM variants, whereas ovarian, gastric, colorectal, and other cancer risks require more conservative interpretation.Therapeutic implications also remain gene-and context-dependent, as the clinical benefit of poly (ADP-ribose) polymerase inhibitors appears less consistent in ATM-altered tumors than in BRCA1/2-altered tumors.In this review, we summarize the biological functions of ATM, the clinical implications of biallelic and monoallelic pathogenic germline variants, cancer-specific risk estimates, current surveillance recommendations, therapeutic implications, and genetic counseling considerations.This review aims to support evidence-based interpretation and clinical management of Korean patients carrying pathogenic germline ATM variants.