Variant: NM_000051.4(ATM):c.2508dup (p.Ser837fs)

CA6265054

646712 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 836339ea-0018-4861-90d6-2771e4d4c3f8

Approved on: 2024-11-26

Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.2508dup
NM_000051.4(ATM):c.2508dup (p.Ser837fs)
NC_000011.10:g.108267212dup
CM000673.2:g.108267212dup
NC_000011.9:g.108137939dup
CM000673.1:g.108137939dup
NC_000011.8:g.107643149dup
NG_009830.1:g.49381dup
ENST00000452508.7:c.2508dup
ENST00000713593.1:c.*1979dup
ENST00000278616.9:c.2508dup
ENST00000682516.1:n.2642dup
ENST00000683174.1:n.2658dup
ENST00000683605.1:n.2003dup
ENST00000684037.1:c.*1443dup
ENST00000527805.6:c.2508dup
ENST00000675595.1:c.2343dup
ENST00000675843.1:c.2508dup
ENST00000278616.8:c.2508dup
ENST00000452508.6:c.2508dup
ENST00000527805.5:c.2508dup
NM_000051.3:c.2508dup
NM_001351834.1:c.2508dup
NM_001351834.2:c.2508dup

Pathogenic

• Met criteria codes: PVS1 PM3 PM5_Supporting PM2_Supporting

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.2508dup (p.Ser837Ilefs*5) variant in ATM is a frameshift 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 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.2.1.1. 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, PM2_Supporting)

Met criteria codes

• PVS1: The c.2508dup (Ser837IlefsTer5) (NM_000051.4) variant in ATM is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay (PVS1).
• PM3: This variant has been detected in 1 individual with Ataxia-Telangiectasia (PMID: 26896183). 2 POINTS: Phenotype confident, phase unknown, w/ ATM c.2250G>A (Clinvar consensus VLP/P, not yet curated by VCEP).
• 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).
• PM2_Supporting: This variant is absent from gnomAD v.2.1.1 (PM2_Supporting).