ATM – Hereditary Nonpolyposis Colorectal Cancer

Pathogenic ATM variants have been identified in autosomal dominant fashion in a small subset of individuals with clinical suspicion of hereditary nonpolyposis colorectal cancer (HNPCC). In a cohort of 1,205 unrelated probands, opportunistic testing of a phenotype-driven panel revealed 4 carriers of germline ATM pathogenic variants among 51 individuals with mismatch repair–proficient colorectal tumors (PMID:30927264), including one recurrent missense allele c.8560C>T (p.Arg2854Cys) (PMID:32522261). No affected relatives with segregating ATM variants have been reported in these cohorts.

The ATM c.5557G>A (p.Asp1853Asn) polymorphism was associated with increased cancer occurrence in MLH1/MSH2 mutation carriers, with 92% penetrance in ATM Asp1853N carriers versus 57.5% in Asp1853 homozygotes (PMID:11093816). However, direct functional assays of ATM variants in colonic epithelial models are lacking, and ATM’s role appears modulatory rather than causative in HNPCC. Overall, the limited number of probands, absence of segregation data, and lack of contextual functional concordance support a Limited gene–disease association. ATM testing may yield incidental findings but has uncertain clinical utility for HNPCC-specific panels.

References

• International journal of cancer • 2019 • Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels. PMID:30927264
• Journal of translational medicine • 2020 • A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection. PMID:32522261
• International journal of cancer • 2000 • A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer. PMID:11093816

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