Variant: NM_000051.4(ATM):c.5236G>A (p.Gly1746Arg)

CA16613442

407510 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 4f737153-e8dd-4e1e-9a3f-07bad4253908

Approved on: 2025-09-03

Published on: 2025-09-15

HGVS expressions

NM_000051.4:c.5236G>A
NM_000051.4(ATM):c.5236G>A (p.Gly1746Arg)
NC_000011.10:g.108301706G>A
CM000673.2:g.108301706G>A
NC_000011.9:g.108172433G>A
CM000673.1:g.108172433G>A
NC_000011.8:g.107677643G>A
NG_009830.1:g.83875G>A
ENST00000452508.7:c.5236G>A
ENST00000713593.1:c.*4707G>A
ENST00000278616.9:c.5236G>A
ENST00000683174.1:n.6720G>A
ENST00000683524.1:n.460G>A
ENST00000684152.1:n.950G>A
ENST00000527805.6:c.*300G>A
ENST00000675595.1:c.*300G>A
ENST00000675843.1:c.5236G>A
ENST00000278616.8:c.5236G>A
ENST00000452508.6:c.5236G>A
ENST00000524792.5:n.1451G>A
ENST00000533690.5:n.640G>A
ENST00000534625.1:n.465G>A
NM_000051.3:c.5236G>A
NM_001351834.1:c.5236G>A
NM_001351834.2:c.5236G>A

Pathogenic

• Met criteria codes: PM3_Supporting PM2_Supporting PM5_Supporting PVS1

• Not Met criteria codes: PP3

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

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.5236G>A (p.Gly1746Arg) variant in ATM is a missense variant observed to cause a 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 (Ambry internal data). 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 was observed in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 in 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(RNA), PM5_Supporting, PM3_Supporting, PM2_Supporting)

Met criteria codes

• PM3_Supporting: This variant has been detected in 1 individual with ataxia-telangiectasia (PMID:26896183, PM3_Supporting).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 in European (non-Finnish) population, which is lower than the ClinGen HBOP VCEP threshold (<0.00001) for PM2_Supporting, meeting this criterion.
• PM5_Supporting: This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious.
• PVS1: Ambry RNA data: 1 RNA case (Heterozygous) picked up r.5178_5319del142 p.V1727Ffs*2 at 40% PSI . This event is completely absent from our control cohort (n>300). Less than 3% of normal spliced reads came from the variant allele. (PVS1 (RNA))

Not Met criteria codes

• PP3: N/A - PVS1