ATM

Chr 11ADSomaticAR

ATM serine/threonine kinase

Also known as: AT1, ATA, ATC, ATD, ATDC, ATE, TEL1, TELO1

NCBI Gene: 472 ENSG00000149311 UniProt: Q13315 OMIM: 607585

The ATM protein is a cell cycle checkpoint kinase that phosphorylates key downstream proteins including p53, BRCA1, and CHK2 to control DNA damage response and maintain genome stability. Biallelic mutations cause ataxia-telangiectasia, an autosomal recessive disorder, while heterozygous mutations confer dominant susceptibility to breast cancer. The pathogenic mechanism involves dominant-negative effects for cancer predisposition and loss of function for ataxia-telangiectasia.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/Somatic/ARLOEUF 0.715 OMIM phenotypes

Clinical Summary— ATM

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Gene-Disease Validity (ClinGen)

ataxia telangiectasia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 4.82

OE 0.60 (0.51–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.10Z-score

OE missense 0.92 (0.88–0.96)

1411 obs / 1532.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.51–0.71)

0≤0.351.4

Missense OE?0.92 (0.88–0.96)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 103 / 171.0Missense obs/exp: 1411 / 1532.7Syn Z: -0.86

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveATM-related cancerLOFAD

definitiveATM-related ataxia-telangiectasiaLOFAR

This gene — mechanism propensity

0.6552th %ile

GOF

0.4381th %ile

LOF

0.3261th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDominant negative ATM mutations in breast cancer families1

LOFThis study examined the cancer incidence of individuals with heterozygous pathogenic variants in over 120 families with ataxia telangiectasia (A-T). The cancer incidence in adult blood relatives of A-T individuals were compared to their adult spouses. The adjusted cancer rate ratio was 1.6 for males2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References