Variant: NM_000051.4(ATM):c.5692C>T (p.Arg1898Ter)

CA6265757

482526 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 34d24ddc-0aa5-4b5e-8bd3-2718b7b7ed8c

Approved on: 2024-11-26

Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.5692C>T
NM_000051.4(ATM):c.5692C>T (p.Arg1898Ter)
NC_000011.10:g.108307914C>T
CM000673.2:g.108307914C>T
NC_000011.9:g.108178641C>T
CM000673.1:g.108178641C>T
NC_000011.8:g.107683851C>T
NG_009830.1:g.90083C>T
NG_054724.1:g.166919G>A
ENST00000452508.7:c.5692C>T
ENST00000713593.1:c.*5163C>T
ENST00000278616.9:c.5692C>T
ENST00000525056.2:n.111C>T
ENST00000682286.1:n.449C>T
ENST00000682302.1:n.110C>T
ENST00000683174.1:n.7176C>T
ENST00000683524.1:n.916C>T
ENST00000684152.1:n.1406C>T
ENST00000527805.6:c.*756C>T
ENST00000675595.1:c.*756C>T
ENST00000675843.1:c.5692C>T
ENST00000278616.8:c.5692C>T
ENST00000452508.6:c.5692C>T
ENST00000524792.5:n.1907C>T
ENST00000529588.5:c.187-2246C>T
ENST00000533690.5:n.1096C>T
NM_000051.3:c.5692C>T
NM_001351834.1:c.5692C>T
NM_001351834.2:c.5692C>T

Pathogenic

• Met criteria codes: PM3_Strong PM5_Supporting PVS1

• Not Met criteria codes: PM2

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.5692 C>T (p.Arg1898*) variant in ATM is a nonsense variant predicted 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. 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. This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID: 17124347, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003268 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the 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)

Met criteria codes

• PM3_Strong: This variant has been detected in 2 unrelated individuals with Ataxia-Telangiectasia (PMID: 17124347, 26896183).
• 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 (PM5_Supporting).
• PVS1: The c.5692 C>T (p.Arg1898*) (NM_000051.4) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay (PVS1).

Not Met criteria codes

• PM2: The highest minor allele frequency in gnomAD v2.1.1 is 0.00003268 (1/30598 alleles) in South Asian population, which is higher than the ClinGen HBOP VCEP threshold (>.001%, ) for PM2_Supporting.