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 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.590G>A (p.Gly197Glu)

CA6264634

420008 (ClinVar)

Gene: ATM
Condition: ATM-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b2b6e72f-83b3-4822-b821-a99760d4d12e
Approved on: 2024-11-26
Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.590G>A
NM_000051.4(ATM):c.590G>A (p.Gly197Glu)
NC_000011.10:g.108244046G>A
CM000673.2:g.108244046G>A
NC_000011.9:g.108114773G>A
CM000673.1:g.108114773G>A
NC_000011.8:g.107619983G>A
NG_009830.1:g.26215G>A
ENST00000452508.7:c.590G>A
ENST00000713593.1:c.*61G>A
ENST00000278616.9:c.590G>A
ENST00000682430.1:n.689G>A
ENST00000682516.1:n.724G>A
ENST00000682956.1:n.724G>A
ENST00000683100.1:n.2268G>A
ENST00000683174.1:n.740G>A
ENST00000683605.1:n.85G>A
ENST00000684037.1:c.590G>A
ENST00000684061.1:n.724G>A
ENST00000684179.1:n.559G>A
ENST00000527805.6:c.590G>A
ENST00000675595.1:c.425G>A
ENST00000675843.1:c.590G>A
ENST00000278616.8:c.590G>A
ENST00000452508.6:c.590G>A
ENST00000527805.5:c.590G>A
ENST00000527891.5:c.425G>A
NM_000051.3:c.590G>A
NM_001351834.1:c.590G>A
NM_001351834.2:c.590G>A
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Uncertain Significance

Met criteria codes 1
PM3
Not Met criteria codes 3
BP4 PP3 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 1.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hereditary Breast, Ovarian and Pancreatic Cancer VCEP
The c.590G>A variant in ATM is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 197 (p.Gly197Glu). This variant has been detected in at least two individuals with Ataxia-Telangiectasia (PMID: 18846412, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002288 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.66, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance 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)
Met criteria codes
PM3
2 points were assigned from 2 homozygous individuals from the literature with consistent phenotypes. The first patient corresponds to an 18-year-old patient who exhibited dystonia as the main symptom rather than classic ataxia. The patient was homozygous for the variant. Prominent oromandibular dystonia and a unique presentation of telangiectasia on the posterior pharyngeal wall were noted. The patient did not show the usual signs of cerebellar ataxia or ocular motor apraxia typical of A-T. ATM kinase activity was retained at a low level and consequently so was ATM function, as measured by a normal level of chromosomal radiosensitivity in the patient’s blood lymphocytes [PMID: 18846412 - Note: this patient is mentioned in other publications, such as 30549301 and 37009283] . The second patient is a 20 y.o. individual (~20 y.o., different from the one referenced above). The patient is homozygous for the variant, with detectable ATM levels and activity. Adj ATNEST total = 83.11
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.66, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. No predicted effects in splicing (SpliceAI=0)
PP3
The computational predictor REVEL gives a score of 0.66, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. No predicted effects in splicing (SpliceAI=0)
PM2
The variant is not rare. The highest MAF observed is 0.0002288 (SA subpopulation in gnomAD) with 5/16238 alleles.
Curation History
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