Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000051.4(ATM):c.7355T>C (p.Leu2452Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA382559953

481101 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0d34d5a3-4333-4679-b03f-0ee4e7269d8b

Approved on: 2025-06-11

Published on: 2025-07-10

HGVS expressions

NM_000051.4:c.7355T>C

NM_000051.4(ATM):c.7355T>C (p.Leu2452Pro)

NC_000011.10:g.108330261T>C

CM000673.2:g.108330261T>C

NC_000011.9:g.108200988T>C

CM000673.1:g.108200988T>C

NC_000011.8:g.107706198T>C

NG_009830.1:g.112430T>C

NG_054724.1:g.144572A>G

ENST00000452508.7:c.7355T>C

ENST00000713593.1:c.*6826T>C

ENST00000278616.9:c.7355T>C

ENST00000525056.2:n.1774T>C

ENST00000525537.3:n.312T>C

ENST00000638786.2:n.192T>C

ENST00000682286.1:n.2112T>C

ENST00000682302.1:n.1773T>C

ENST00000683174.1:n.8839T>C

ENST00000683524.1:n.2579T>C

ENST00000684152.1:n.3069T>C

ENST00000684447.1:n.1818T>C

ENST00000527805.6:c.*2419T>C

ENST00000675595.1:c.*2490T>C

ENST00000675843.1:c.7355T>C

ENST00000278616.8:c.7355T>C

ENST00000452508.6:c.7355T>C

ENST00000524792.5:n.3570T>C

ENST00000525729.5:c.641-21190A>G

ENST00000533690.5:n.2759T>C

NM_000051.3:c.7355T>C

NM_001330368.1:c.641-21190A>G

NM_001351110.1:c.*38+4959A>G

NM_001351834.1:c.7355T>C

NM_001330368.2:c.641-21190A>G

NM_001351110.2:c.*38+4959A>G

NM_001351834.2:c.7355T>C

Likely Pathogenic

PP3 PM2_Supporting PS3_Supporting PM3_Strong

Evidence Links 0

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.7355T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 2452 (p.Leu2452Pro). This variant has been detected in at least two individuals with Ataxia-Telangiectasia (PMIDs: 19431188, 26896183). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 in the European (non-Finnish) population, which is lower than the HBOP threshold (≤0.00001) for PM2_Supporting, meeting this criterion. Western blotting in ATM null cells transfected with cDNA carrying this variant showed inactive phosphorylation of ATM downstream targets as compared to wild-type controls, indicating that this variant impacts protein function (PMID: 19431188). The computational predictor REVEL gives a score of 0.914, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Strong, PM2_Supporting, PS3_Supporting, PP3)

PP3

The computational predictor REVEL gives a score of 0.914,which is above the threshold of ≥.733, evidence that correlates with impact to ATM function

PM2_Supporting

This variant is absent in gnomAD v2.1.1

PS3_Supporting

Experimental studies showed that this variant has no ATM kinase activity compared to wild type in an expression system.

PM3_Strong

This Variant has been detected in atleast 2 individuals with Ataxia-Telangiectasia(PMID:19431188,: 26896183)

Curation History

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