The ATM c.8362C>T (p.His2788Tyr) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by 2 clinical laboratories.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, and the observed population frequency is therefore below the ATM PM2_Supporting threshold of <=0.001%.2 A multiplex functional study classified p.His2788Tyr as non-functional with high confidence, but the available data are based on olaparib fitness assays and do not yet establish the ATM-specific rescue framework required to apply ATM PS3 or BS3 without manual review.3 REVEL is 0.669, which is below the ATM PP3 threshold of >0.7333 and above the ATM BP4 missense threshold of <=0.249, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, below the benign splicing threshold of <=0.1.4
Final classification
VUS
PM2
ATM
c.8362C>T
p.His2788Tyr
This variant
The ATM c.8362C>T (p.His2788Tyr) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by 2 clinical laboratories.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically and no rule matched the adjudicated criteria.
Classification rationale
PM2
VUS
ATM c.8362C>T
PM2
→
VUS
3
PMID:40580951 ↗vcep_s_u_p_p_l___t_a_b_l_e_s_1___p_m_i_d___4_0_5_8_0_9_5_1cspec ↗
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 · 11 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
PM2
Supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM PM2_Supporting threshold of <=0.001%.
Absent from gnomAD v2.1Absent from gnomAD v4.1ATM PM2 applies at Supporting strength for frequency <=0.001% in gnomAD v4
Assessed · not applied
· 6 not met · 5 not assessed
Pathogenic
PS1
No pathogenic or likely pathogenic reference variant producing the same amino acid change or the same splice event was identified, so PS1 is not supported.
PS3
A multiplex functional study classified p.(His2788Tyr) as non-functional with high confidence, but the available assay measures olaparib-related cell fitness and does not clearly demonstrate failure to rescue both an ATM-specific feature and radiosensitivity as required for ATM PS3.
PS4
No case-control study or enrichment data showing a statistically significant excess of this variant in affected individuals were identified, so PS4 is not met.
PM3
No data were identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 cannot be assessed.
PP1
No segregation data were identified for this variant in affected relatives, so PP1 cannot be applied.
PP3
REVEL is 0.669, which is below the ATM PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the splicing threshold of >=0.2.
Benign
BA1
This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM BA1 threshold of >0.5%.
BS1
This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM BS1 threshold of >0.05%.
BS3
No ATM VCEP-compatible benign functional evidence showing rescue of an ATM-specific feature or radiosensitivity was identified.
BP2
No co-occurrence data were identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual, so BP2 cannot be assessed.
BP4
REVEL is 0.669, which is above the ATM BP4 missense threshold of <=0.249, so benign missense prediction is not supported.
N/A · 16
PVS1 · 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
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links