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
ATM
Final classification
VUS
ATM c.2222A>G · p.Tyr741Cys
ATM
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
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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