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Variant: NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys)

CA287019

127459 (ClinVar)

Gene: ATM
Condition: hereditary breast cancer
Inheritance Mode: Autosomal dominant inheritance
UUID: a1f4fda0-ab77-4c22-a6be-6dc2f95f8e60
Approved on: 2024-01-25
Published on: 2024-02-14

HGVS expressions

NM_000051.4:c.8494C>T
NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys)
NC_000011.10:g.108345818C>T
CM000673.2:g.108345818C>T
NC_000011.9:g.108216545C>T
CM000673.1:g.108216545C>T
NC_000011.8:g.107721755C>T
NG_009830.1:g.127987C>T
NG_054724.1:g.129015G>A
ENST00000452508.7:c.8494C>T
ENST00000713593.1:c.*7965C>T
ENST00000278616.9:c.8494C>T
ENST00000638786.2:n.1192C>T
ENST00000682286.1:n.3251C>T
ENST00000682302.1:n.2912C>T
ENST00000683174.1:n.9978C>T
ENST00000683524.1:n.3718C>T
ENST00000684152.1:n.3910C>T
ENST00000684180.1:n.968C>T
ENST00000684447.1:n.4987C>T
ENST00000527805.6:c.*3558C>T
ENST00000675595.1:c.*3629C>T
ENST00000675843.1:c.8494C>T
ENST00000278616.8:c.8494C>T
ENST00000452508.6:c.8494C>T
ENST00000524755.5:c.227-10526G>A
ENST00000524792.5:n.4709C>T
ENST00000525729.5:c.641-36747G>A
ENST00000526725.1:n.272-5454G>A
ENST00000527531.5:c.*1196+9097G>A
ENST00000615746.4:c.*1196+9097G>A
NM_000051.3:c.8494C>T
NM_001330368.1:c.641-36747G>A
NM_001351110.1:c.695-10526G>A
NM_001351834.1:c.8494C>T
NR_147053.2:n.2301+9097G>A
NM_001330368.2:c.641-36747G>A
NM_001351110.2:c.695-10526G>A
NM_001351834.2:c.8494C>T
NR_147053.3:n.2299+9097G>A

Likely Pathogenic

Met criteria codes 3
PS3_Supporting PP3 PM3_Strong
Not Met criteria codes 1
PM2

Evidence Links 0

Expert Panel

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 1.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hereditary Breast, Ovarian and Pancreatic Cancer VCEP
The c.8494C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2832 (p.Arg2832Cys). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 26896183, 22017321, 26846839). The highest minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor, Revel (Score: 0.83), predicts a damaging effect on ATM function. Additionally, experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Strong, PP3, PS3_supporting)
Met criteria codes
PS3_Supporting
Experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type
PP3
REVEL predicted the score of 0.83 which is above thresholds defined by the HBOP VCEP for PP3
PM3_Strong
This variant has been detected in atleast 3 individuals with Ataxia-Telangiectasia.( PMID: 26896183, 22017321, 26846839)
Not Met criteria codes
PM2
This variant has a minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met).
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