Variant: NM_000051.4(ATM):c.3576G>A (p.Lys1192=)

CA193897

3035 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 13cd2f77-0719-42e0-8f30-1b421f7e69fa

Approved on: 2024-11-26

Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.3576G>A
NM_000051.4(ATM):c.3576G>A (p.Lys1192=)
NC_000011.10:g.108281168G>A
CM000673.2:g.108281168G>A
NC_000011.9:g.108151895G>A
CM000673.1:g.108151895G>A
NC_000011.8:g.107657105G>A
NG_009830.1:g.63337G>A
ENST00000452508.7:c.3576G>A
ENST00000713593.1:c.*3047G>A
ENST00000278616.9:c.3576G>A
ENST00000683174.1:n.3726G>A
ENST00000527805.6:c.3576G>A
ENST00000675595.1:c.3411G>A
ENST00000675843.1:c.3576G>A
ENST00000278616.8:c.3576G>A
ENST00000452508.6:c.3576G>A
ENST00000527805.5:c.3576G>A
NM_000051.3:c.3576G>A
NM_001351834.1:c.3576G>A
NM_001351834.2:c.3576G>A

Pathogenic

• Met criteria codes: PM3_Very Strong PVS1_Strong

• 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. 3576G>A (p.Lys1192=) variant is a synonymous (silent) variant in ATM. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID: 9887333, 21965147; Ambry internal data). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 21965147, 26896183, 30819809). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000035 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). 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 Variant Curation Expert Panel. (PVS1_Strong (RNA), PM3_Very Strong)

Met criteria codes

• PM3_Very Strong: This variant has been detected in atleast 6 individuals with Ataxia-Telangiectasia.(PMID: 21965147, 26896183, 30819809)
• PVS1_Strong: The c. 3576G>A (p.Lys1192=) variant is a synonymous (silent) variant in ATM. This alteration is demonstrated through RNA studies to result in abnormal splicing leading to skipping of exon 24.(Ambry internal data,PMID: 21965147, 9887333)

Not Met criteria codes

• PM2: This variant has a minor allele frequency in gnomAD v2.1.1 of 0.003% in the European non finnish population which is above the threshold of 0.001% (PM2_Supporting, BS1, and BA1 are not met).