ATM

Chr 11ADSomaticAR

ATM serine/threonine kinase

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

NCBI Gene: 472 ENSG00000149311 UniProt: Q13315

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]

Primary Disease Associations & Inheritance

{Breast cancer, susceptibility to}MIM #114480

ADSomatic

Ataxia-telangiectasiaMIM #208900

Lymphoma, B-cell non-Hodgkin, somatic

Lymphoma, mantle cell, somatic

T-cell prolymphocytic leukemia, somatic

UniProtAtaxia telangiectasia

600

ClinVar variants

112

Pathogenic / LP

0.00

pLI score

Active trials

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

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

112 Pathogenic / Likely Pathogenic· 354 VUS of 600 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.71LOEUF

pLI 0.000

Z-score 4.82

OE 0.60 (0.51–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.10Z-score

OE missense 0.92 (0.88–0.96)

1411 obs / 1532.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.60 (0.51–0.71)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.88–0.96)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05

0≤1.21.6

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

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic90

Likely Pathogenic22

VUS354

Likely Benign131

Benign1

Conflicting2

Pathogenic

Likely Pathogenic

354

VUS

131

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	68	0	22	0	90
Likely Pathogenic	15	3	4	0	22
VUS	1	305	46	2	354
Likely Benign	0	5	86	40	131
Benign	0	0	1	0	1
Conflicting	—				2
Total	84	313	159	42	600

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ATM · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ATM-related cancer

definitive

ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure

Cancer

G2P ↗

ATM-related ataxia-telangiectasia

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. DisordersSkinCancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

ATM SERINE/THREONINE KINASE; ATM

MIM #607585 · *

{Breast cancer, susceptibility to}

MIM #114480