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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000051.4(ATM):c.1355del (p.Thr452fs)

CA165539

141474 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1a5b309b-b5a6-4d54-871c-1b0dbeb0e2dd

Approved on: 2024-01-25

Published on: 2024-02-14

HGVS expressions

NM_000051.4:c.1355del

NM_000051.4(ATM):c.1355del (p.Thr452fs)

NC_000011.10:g.108250820del

CM000673.2:g.108250820del

NC_000011.9:g.108121547del

CM000673.1:g.108121547del

NC_000011.8:g.107626757del

NG_009830.1:g.32989del

ENST00000452508.7:c.1355del

ENST00000713593.1:c.*826del

ENST00000278616.9:c.1355del

ENST00000682516.1:n.1489del

ENST00000682956.1:n.1489del

ENST00000683174.1:n.1505del

ENST00000683605.1:n.850del

ENST00000684037.1:c.*290del

ENST00000684061.1:n.1489del

ENST00000684179.1:n.1324del

ENST00000527805.6:c.1355del

ENST00000675595.1:c.1190del

ENST00000675843.1:c.1355del

ENST00000278616.8:c.1355del

ENST00000452508.6:c.1355del

ENST00000527805.5:c.1355del

NM_000051.3:c.1355del

NM_001351834.1:c.1355del

NM_001351834.2:c.1355del

Pathogenic

PM3_Supporting PM5_Supporting PM2_Supporting PVS1

PP3

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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.1355del (p.Thr452AsnfsTer21) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 9463314, 10234507, 26896183). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Supporting, PM2_Supporting).

PM3_Supporting

This variant has been detected in an individual with Ataxia-Telangiectasia in the compound heterozygous state with a missense variant (c.4394T>C (p.Leu1465Pro) - preliminary VUS, no functional data) confirmed in trans by parental testing (PMID: 9463314, 10234507, 26896183: 1 points - PM3_Supporting)

PM5_Supporting

This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious.

PM2_Supporting

This variant is absent from gnomAD v2.1.1.

PVS1

The c.1355del (p.Thr452AsnfsTer21) variant in ATM is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/62 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism.

PP3

No impact on splicing per Splice AI.

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