Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: ATM vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: ATM CSPEC Genes: [ 'ATM' ] * Message MONDOs: MONDO:0700270 CSPEC MONDO: [ 'MONDO:0016419', 'MONDO:0008840', 'MONDO:0018266' ]
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000051.4(ATM):c.5228C>T (p.Thr1743Ile)

CA286882

127403 (ClinVar)

Gene: ATM
Condition: ATM-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6ecae11f-0052-46e5-8b68-b07412d09b04
Approved on: 2025-06-11
Published on: 2025-07-10

HGVS expressions

NM_000051.4:c.5228C>T
NM_000051.4(ATM):c.5228C>T (p.Thr1743Ile)
NC_000011.10:g.108301698C>T
CM000673.2:g.108301698C>T
NC_000011.9:g.108172425C>T
CM000673.1:g.108172425C>T
NC_000011.8:g.107677635C>T
NG_009830.1:g.83867C>T
ENST00000452508.7:c.5228C>T
ENST00000713593.1:c.*4699C>T
ENST00000278616.9:c.5228C>T
ENST00000683174.1:n.6712C>T
ENST00000683524.1:n.452C>T
ENST00000684152.1:n.942C>T
ENST00000527805.6:c.*292C>T
ENST00000675595.1:c.*292C>T
ENST00000675843.1:c.5228C>T
ENST00000278616.8:c.5228C>T
ENST00000452508.6:c.5228C>T
ENST00000524792.5:n.1443C>T
ENST00000533690.5:n.632C>T
ENST00000534625.1:n.457C>T
NM_000051.3:c.5228C>T
NM_001351834.1:c.5228C>T
NM_001351834.2:c.5228C>T
More

Pathogenic

Met criteria codes 3
PM3_Very Strong PS3_Supporting PP3
Not Met criteria codes 4
PM2 BS1 BP4 BA1

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 1.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hereditary Breast, Ovarian and Pancreatic Cancer VCEP
The c.5228C>T variant in ATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 1743 (p.Thr1743Ile). This variant has been detected in numerous unrelated individuals with Ataxia-Telangiectasia (PMIDs: 19147735, 21792198, 26896183, 31921190). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008476 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). Western blotting in ATM null cells transfected with cDNA carrying this variant showed a reduction in phosphorylation of ATM downstream targets as compared to wild-type controls, indicating that this variant impacts protein function (PMID: 19431188). The computational predictor REVEL gives a score of 0.835 which is above the threshold of 0.7333, evidence that correlates with impact to ATM function. 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. (PM3_VeryStrong, PS3_Supporting, PP3).
Met criteria codes
PM3_Very Strong
This variant has been detected in numerous individuals with Ataxia-Telangiectasia (PMIDs: 31921190, 26896183, 21792198, 19147735)
PS3_Supporting
Western blotting in ATM null cells transfected with cDNA carrying this variant showed a reduction in phosphorylation of ATM downstream targets as compared to wild-type controls, indicating that this variant impacts protein function (PMID: 19431188).
PP3
The computational predictor REVEL gives a score of 0.835 which is above the threshold of 0.7333, evidence that correlates with impact to ATM function (PP3).
Not Met criteria codes
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004005 (1/24970) which exceeds the PM2 threshold of 0.00001 (PM2_Supporting not met).
BS1
The filtering allele frequency (the lower threshold of the 95% CI of 2/113458) is 0.00001123 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen HBOP VCEP threshold (>0.0005) for BS1, and therefore does not meet this criterion (BS1 not met).
BP4
SpliceAI 0.03 AL, not significant.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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