The ATM c.2222A>G (p.Tyr741Cys) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign submissions.1 This variant is present in population databases at low frequency, including gnomAD v4.1 at 0.00217% overall (35/1,611,122 alleles) with a highest observed subpopulation frequency of 0.00447% in East Asian individuals, which is above the ATM PM2_Supporting threshold of <=0.001% and below the BS1 and BA1 thresholds.2 Computational evidence is mixed: SpliceAI predicts possible splice impact with a maximum delta score of 0.29, supporting ATM PP3_Supporting, whereas REVEL is low at 0.153 and BayesDel is negative at -0.288378, which argues against a damaging missense effect but does not resolve the predicted splice concern.3
Final classification
VUS
PP3
ATM
c.2222A>G
p.Tyr741Cys
This variant
The ATM c.2222A>G (p.Tyr741Cys) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign submissions.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PP3
VUS
ATM c.2222A>G
PP3
→
VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PP3
supporting
review
Pathogenic
SpliceAI predicts possible splice impact with a maximum delta score of 0.29, which is above the ATM PP3 splicing threshold of >=0.2 for missense variants. Although REVEL is low at 0.153 and BayesDel is negative at -0.288378, the ATM VCEP rule allows PP3_Supporting for predicted splice impact in missense variants, so PP3_Supporting is met with caution pending RNA confirmation.
SpliceAI max delta score 0.29.REVEL score 0.153.BayesDel score -0.288378.
Assessed · not applied
· 4 not met · 6 not assessed
Pathogenic
PS3
No validated ATM functional study was identified showing that this variant fails to rescue an ATM-specific cellular feature or radiosensitivity, so PS3 could not be applied.
PS4
This variant has been reported in ClinVar and once in COSMIC, but no case-control study or robust enrichment data in affected individuals were identified to support PS4.
PM2
Population frequency does not meet the ATM PM2_Supporting threshold.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 could not be assessed.
PP1
No segregation data were identified for this variant, so PP1 could not be applied.
Benign
BA1
Population frequency is well below the ATM BA1 threshold.
BS1
Population frequency is below the ATM BS1 threshold.
BS3
No validated ATM functional study was identified showing normal or rescued function for this variant, so BS3 could not be applied.
BP2
No evidence was identified that this variant co-occurs in trans with a pathogenic ATM variant in an unaffected individual, so BP2 could not be assessed.
BP4
REVEL is low at 0.153 and BayesDel is negative at -0.288378, which would support a benign missense interpretation, but SpliceAI predicts possible splice impact with a maximum delta score of 0.29, above the ATM no-splice-impact threshold of <=0.1.
N/A · 17
PVS1 · PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.1724e-05; MAF= 0.00217%, 35/1611122 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.47007e-05; MAF= 0.00447%, 2/44742 alleles, homozygotes = 0); grpmax FAF= 1.965e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.41539e-05; MAF= 0.00142%, 4/282608 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100492; MAF= 0.01005%, 2/19902 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0022%
· 35 / 1,611,122
0 hom · FAF 0.002%
0 hom · FAF 0.002%
East Asian 2 / 44,742 |
0.0045% |
European (non-Finnish) 32 / 1,178,146 |
0.0027% |
Remaining individuals 1 / 62,304 |
0.0016% |
+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0014%
· 4 / 282,608
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
East Asian 2 / 19,902 |
0.01% |
European (non-Finnish) 2 / 129,084 |
0.0015% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (3 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.29). REVEL score = 0.153. BayesDel score = -0.288378.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105123853, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links