ATM – Hereditary Breast Carcinoma

ATM encodes a serine–threonine kinase central to the DNA damage response, acting as a sensor and transducer of double-strand breaks. Heterozygous loss-of-function (LoF) and deleterious missense variants in ATM have been implicated in increased breast cancer susceptibility, positioning ATM as a moderate-penetrance, autosomal dominant risk gene in familial breast carcinoma.

Large case–control series have established that ATM LoF carriers have markedly elevated breast cancer risk. In the GENESIS study of 1,207 BRCA1/2-negative familial breast cancer probands, rare ATM LoF variants conferred an odds ratio of 17.4 vs 1.6 for missense variants (pHet = 0.002) (PMID:30303537). A separate Australian multiple-case cohort found the IVS10-6T>G allele at similar frequencies in 495 familial cases and population controls, suggesting this splice variant does not act as a high-penetrance allele but may modify risk in combination with other genes (PMID:15217508).

Independent clinical series corroborate ATM’s role: a Romanian cohort of 411 hereditary breast cancer patients identified pathogenic ATM variants in 33% of non-BRCA carriers (PMID:37239058). Moreover, screening of 443 familial breast cancer pedigrees versus 521 controls revealed 12 ATM mutations in cases and only two in controls (RR 2.37; P = 0.0003) (PMID:16832357).

Functional assays demonstrate ATM’s mechanistic concordance with breast cancer phenotypes. ATM phosphorylates BRCA1 at Ser1387, Ser1423 and Ser1457 in response to ionizing radiation; loss of ATM abrogates this modification and impairs DNA repair checkpoints (PMID:10866324). ATM also phosphorylates the Nijmegen breakage syndrome protein Nibrin (NBS1) on Ser343, linking ATM-NBS1 signalling in S-phase checkpoint control (PMID:10802669).

Despite strong genetic and experimental concordance, some ATM alleles act as low-penetrance or risk-modifier variants. The IVS10-6T>G and other common polymorphisms have not shown significant enrichment in high-risk families, underscoring the need for careful variant classification in clinical testing (PMID:15217508).

Collectively, genetic and functional data support a Moderate ClinGen classification for the ATM–hereditary breast carcinoma association, with robust evidence from >1,200 probands, multi-family analyses, and concordant mechanistic studies. ATM testing within multigene panels informs risk estimation, surveillance, and therapeutic decisions in familial breast cancer.

Key Take-home: Heterozygous LoF and pathogenic missense ATM variants confer moderate‐penetrance risk for hereditary breast carcinoma and should be incorporated into clinical risk assessment and management.

References

• International journal of cancer • 2019 • Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing PMID:30303537
• Breast cancer research : BCR • 2004 • Frequency of the ATM IVS10-6T-->G variant in Australian multiple-case breast cancer families PMID:15217508
• Nature genetics • 2006 • ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles PMID:16832357
• Cancer research • 2000 • Role for ATM in DNA damage-induced phosphorylation of BRCA1 PMID:10866324
• Nature genetics • 2000 • ATM-dependent phosphorylation of nibrin in response to radiation exposure PMID:10802669

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