The ATM c.419A>T (p.(Asp140Val), p.(D140V)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its frequency of 0 is below the ATM PM2_Supporting threshold of less than or equal to 0.001%.2 In an ATM supplementary functional dataset, p.(D140V) was classified as Functional with High confidence, but the available retrieved evidence does not provide the assay-level rescue details required to assign ATM PS3 or BS3 in this pass.3 Computational evidence supports a damaging missense effect: REVEL is 0.815, above the ATM PP3 threshold of greater than 0.7333, BayesDel is 0.278827, and SpliceAI shows no significant splice impact with a maximum delta score of 0.06.4
Final classification
VUS
PM2PP3
ATM
c.419A>T
p.Asp140Val
This variant
The ATM c.419A>T (p.(Asp140Val), p.(D140V)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3
VUS
ATM c.419A>T
PM2 + PP3
→
VUS
3
vcep_suppl_tables1_pmid_40580951cspec ↗
4
revelbayesdelspliceai ↗cspec ↗
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 · 2 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. A frequency of 0 is below the ATM PM2_Supporting threshold of less than or equal to 0.001%, so PM2_Supporting is met.
gnomAD v4.1 absentgnomAD v2.1 absentATM PM2 threshold <=0.001%
PP3
supporting
Pathogenic
This missense variant has a REVEL score of 0.815, which is above the ATM PP3 threshold of greater than 0.7333. SpliceAI shows a maximum delta score of 0.06, which does not suggest a splice effect, so the computational evidence supports a damaging missense effect and PP3 is met at supporting strength.
REVEL 0.815SpliceAI max delta 0.06BayesDel 0.278827
Assessed · not applied
· 3 not met · 7 not assessed
Pathogenic
PS1
No pathogenic or likely pathogenic comparator causing the same amino acid change or the same defined splice event was identified from the available ATM-specific materials, so PS1 was not established.
PS3
An ATM supplementary functional dataset lists p.(D140V) as Functional with High confidence, but the available retrieved evidence in this pass does not provide assay-level rescue results for ATM-specific function and radiosensitivity needed to apply ATM PS3.
PS4
No case-control data or enrichment data meeting the ATM PS4 rule were identified.
PM3
No proband data showing this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 points cannot be assigned.
PP1
No family segregation data were identified, so PP1 cannot be applied.
Benign
BA1
This variant is absent from gnomAD v4.1, so its frequency is not above the ATM BA1 threshold of greater than 0.5%.
BS1
This variant is absent from gnomAD v4.1, so its frequency is not above the ATM BS1 threshold of greater than 0.05%.
BS3
An ATM supplementary functional dataset lists p.(D140V) as Functional with High confidence, but the available retrieved evidence in this pass does not show the specific rescue results for ATM-specific activity and radiosensitivity required to assign ATM BS3.
BP2
No co-occurrence data in trans with a pathogenic ATM variant in unaffected individuals were identified, so BP2 points cannot be assigned.
BP4
Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, the REVEL score is 0.815, which is well above the ATM BP4 missense threshold of less than or equal to 0.249.
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.815. BayesDel score = 0.278827.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links