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Ataxia–telangiectasia mutated (ATM) is a serine–threonine kinase that orchestrates signaling and repair of DNA double-strand breaks. Sarcomas (MONDO:0005089) are a heterogeneous group of malignant mesenchymal tumors with known links to defects in DNA damage response pathways. Both germline and somatic ATM variants have been reported in patients with diverse sarcoma subtypes, suggesting ATM disruption contributes to sarcoma pathogenesis. The role of ATM in genomic stability and cell cycle control provides a biologically plausible mechanism for sarcoma predisposition and progression.
The clinical validity of the ATM–sarcoma association is classified as Moderate. Germline ATM variants were identified in 9 of 66 unrelated sarcoma patients (13.6%) in an Asian sporadic cohort (PMID:28878254) and further confirmed in an international series of 312 sarcoma‐suspected patients with pathogenic ATM alleles and tumor second hits (PMID:39594770). No large multigenerational segregation studies are reported, but the replication in independent cohorts supports a moderate level of evidence.
Genetic evidence derives from autosomal dominant inheritance of heterozygous ATM variants predisposing to sarcoma. In a multi‐patient sequencing study of 66 young sporadic sarcoma cases, predicted pathogenic ATM missense and truncating alleles contributed to a 10.6% prevalence in DNA repair genes (PMID:28878254). A prospective germline screen of 312 patients found ATM among 24 genes with pathogenic variants, with somatic second hits detected in tumors (PMID:39594770). No segregation data are available.
The ATM variant spectrum in sarcoma includes predominantly missense and nonsense changes affecting kinase activity. A recurrent germline missense allele c.512A>G (p.Tyr171Cys) was reported in sporadic sarcoma patients (PMID:28878254). Truncating variants and splice‐site mutations are less common but documented. No clear founder variants have been described to date.
Functional evidence for ATM’s role in sarcoma remains limited. ATM is established as a master regulator of the DNA damage response in multiple cellular and animal models, but direct functional studies of ATM loss in sarcoma cell lines or animal sarcoma models have not yet been reported. ATM deficiency plausibly leads to genomic instability, a hallmark of sarcoma oncogenesis.
No studies have conclusively refuted the ATM–sarcoma link. In summary, ATM germline variants contribute moderately to sarcoma risk, and somatic ATM loss likely exacerbates genomic instability in developing tumors. Clinicians should consider ATM sequencing in young sarcoma patients, as identification of ATM variants may inform genetic counseling and potential use of DNA repair–targeted therapies. Key take-home: ATM heterozygous mutations confer a moderate predisposition to sarcoma driven by defective DNA double-strand break repair.
Gene–Disease AssociationModerateGermline ATM variants identified in 9/66 sarcoma probands ([PMID:28878254]) and replicated in 312 suspected sarcoma patients with second hits in tumors ([PMID:39594770]) Genetic EvidenceModerateHeterozygous ATM missense and truncating variants found in 13.6% of 66 sporadic sarcoma patients and confirmed in an independent 312‐patient cohort Functional EvidenceLimitedATM’s DNA damage response role is well established but direct functional models in sarcoma are lacking |