Variant: NM_000051.4(ATM):c.9022C>T (p.Arg3008Cys)

CA294307

142187 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 756eeb9f-e985-4813-90f9-4aa49258e73a

Approved on: 2024-11-26

Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.9022C>T
NM_000051.4(ATM):c.9022C>T (p.Arg3008Cys)
NC_000011.10:g.108365359C>T
CM000673.2:g.108365359C>T
NC_000011.9:g.108236086C>T
CM000673.1:g.108236086C>T
NC_000011.8:g.107741296C>T
NG_009830.1:g.147528C>T
NG_054724.1:g.109474G>A
ENST00000452508.7:c.9022C>T
ENST00000713593.1:c.*8493C>T
ENST00000278616.9:c.9022C>T
ENST00000638786.2:n.1720C>T
ENST00000682286.1:n.3779C>T
ENST00000682302.1:n.3440C>T
ENST00000682569.1:n.2369C>T
ENST00000683174.1:n.10506C>T
ENST00000683524.1:n.4246C>T
ENST00000684152.1:n.4438C>T
ENST00000684180.1:n.1496C>T
ENST00000684447.1:n.5515C>T
ENST00000527805.6:c.*4086C>T
ENST00000675595.1:c.*4157C>T
ENST00000675843.1:c.9022C>T
ENST00000278616.8:c.9022C>T
ENST00000452508.6:c.9022C>T
ENST00000524755.5:c.226+27849G>A
ENST00000524792.5:n.5237C>T
ENST00000525178.5:n.510C>T
ENST00000525729.5:c.640+20561G>A
ENST00000526725.1:n.272-24995G>A
ENST00000527181.1:n.361C>T
ENST00000527531.5:c.*2-9250G>A
ENST00000615746.4:c.*2-9250G>A
NM_000051.3:c.9022C>T
NM_001330368.1:c.640+20561G>A
NM_001351110.1:c.694+20561G>A
NM_001351834.1:c.9022C>T
NR_147053.2:n.1107-9250G>A
NM_001330368.2:c.640+20561G>A
NM_001351110.2:c.694+20561G>A
NM_001351834.2:c.9022C>T
NR_147053.3:n.1105-9250G>A

Likely Pathogenic

• Met criteria codes: PM3_Very Strong PS3_Supporting

• Not Met criteria codes: PP3 PM2 BP4

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.9022C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3008 (p.Arg3008Cys). This variant has been detected in at least 5 individuals with Ataxia-Telangiectasia (PMID: 12552566, 18573109, 25122203, 26896183, 30549301). Additionally, experimental studies showed that this variant impacts ATM kinase activity and radiosensitivity compared to wild type (PMID: 19431188). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as likely 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. (PM3_Very Strong, PS3_Supporting)

Met criteria codes

• PM3_Very Strong: This variant has been detected in atleast 4 individuals with Ataxia-Telangiectasia.(PMID:26896183,12552566,25122203)
• PS3_Supporting: Experimental studies shows that this variant has impact on ATM kinase activity, protein levels and radiosensitivity when compared with wild type (PMID:19431188).

Not Met criteria codes

• PP3: The computational predictor Revel gives a score of 0.519 which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function
• PM2: This variant has a minor allele frequency in gnomAD v2.1.1 of 0.006% in the African population which is above the threshold of 0.001% (PM2_Supporting, BS1, and BA1 are not met).
• BP4: The computational predictor Revel gives a score of 0.519 which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function