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.467G>A (p.Trp156Ter)

CA382525484

634428 (ClinVar)

Gene: ATM (HGNC:472)

Condition: ATM-related cancer predisposition (MONDO:0700270)

Inheritance Mode: Autosomal dominant inheritance

UUID: 1d59175c-fb11-4dcb-9edd-ffdccb9bd5b0

Approved on: 2025-09-25

Published on: 2025-10-20

HGVS expressions

NM_000051.4(ATM):c.467G>A (p.Trp156Ter)

NM_000051.4:c.467G>A

NC_000011.10:g.108235805G>A

CM000673.2:g.108235805G>A

NC_000011.9:g.108106532G>A

CM000673.1:g.108106532G>A

NC_000011.8:g.107611742G>A

NG_009830.1:g.17974G>A

ENST00000452508.7:c.467G>A

ENST00000713593.1:c.467G>A

ENST00000278616.9:c.467G>A

ENST00000682147.1:n.597G>A

ENST00000682430.1:n.566G>A

ENST00000682516.1:n.601G>A

ENST00000682956.1:n.601G>A

ENST00000683174.1:n.617G>A

ENST00000684029.1:c.467G>A

ENST00000684037.1:c.467G>A

ENST00000684061.1:n.601G>A

ENST00000684179.1:n.465+6482G>A

ENST00000527805.6:c.467G>A

ENST00000675595.1:c.331+6482G>A

ENST00000675843.1:c.467G>A

ENST00000278616.8:c.467G>A

ENST00000452508.6:c.467G>A

ENST00000527805.5:c.467G>A

ENST00000527891.5:c.331+6482G>A

ENST00000530958.5:c.467G>A

NM_000051.3:c.467G>A

NM_001351834.1:c.467G>A

NM_001351834.2:c.467G>A

Pathogenic

PM3_Strong PM2_Supporting PVS1 PM5_Supporting

PP3 BP4

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.467G>A (p.Trp156*) variant in ATM gene is a nonsense variant predicted to cause premature stop codon in 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 (p.Arg3047*), as classified by the HBOP VCEP, and it is expected to be more deleterious. This variant has been detected in at least three unrelated individuals with Ataxia-Telangiectasia (PMIDs: 26896183, 34771661, 24954719). 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. In summary, this variant meets criteria to be classified as 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. (PVS1, PM5_Supporting, PM3_Strong, PM2_Supporting)

PM3_Strong

This Variant has been detected in atleast 3 individuals with Ataxia-Telangiectasia CASE 1-Heterozygous with the pathogenic variant c.790delT -2 points (PMID:26896183)(Jackson et al.,) CASE 2- PMID: 34771661-Second variant unknown—1 point CASE 3- PMID: 24954719- Compound het c.1121_1122delAA(Established pathogenic)- 2 points TOTAL-5 points

PM2_Supporting

Allele count=1

PVS1

The c.467G>A (p.Trp156Ter) variant in ATM gene is a nonsense variant observed to cause premature truncation of the protein in exon 5/63 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism.

PM5_Supporting

The c.467G>A (p.Trp156Ter) variant 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 deleterious.

PP3

The computational splicing predictor SpliceAI gives a score of 0.38 for donor loss, supporting neither a deleterious nor benign impact on splicing. This does not impact PVS1 applied at full strength.

BP4

The computational splicing predictor SpliceAI gives a score of 0.38 for donor loss, supporting neither a deleterious nor benign impact on splicing. This does not impact PVS1 applied at full strength.

Curation History

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