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
ATM
Final classification
VUS
ATM c.419A>T · p.Asp140Val
ATM
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 ↗
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 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
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