The ATM c.4397_4398delinsCG (p.Arg1466Pro) variant has been reported in ClinVar, where the overall expert-panel classification is uncertain significance and additional submissions range from uncertain significance to likely pathogenic and pathogenic.1 This variant is absent from gnomAD v4.1 and gnomAD v2.1, which is below the ATM VCEP PM2_supporting population threshold of less than or equal to 0.001%.2 In an ATM VCEP supplementary variant table, the equivalent single-nucleotide representation c.4397G>C (p.Arg1466Pro) is listed as non-functional with high confidence, supporting an abnormal ATM protein effect.3 SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.01, and the equivalent c.4397G>C missense representation has a REVEL score of 0.677 in the ATM VCEP supplementary variant table, which is below the ATM PP3 threshold of greater than 0.7333 and above the BP4 threshold of less than or equal to 0.249.4
Final classification
VUS
PS3PM2
ATM
c.4397_4398delinsCG
p.Arg1466Pro
This variant
The ATM c.4397_4398delinsCG (p.Arg1466Pro) variant has been reported in ClinVar, where the overall expert-panel classification is uncertain significance and additional submissions range from uncertain significance to likely pathogenic and pathogenic.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 supporting, PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PM2
VUS
ATM c.4397_4398delinsCG
PS3 + PM2
→
VUS
3
vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1cspec ↗
4
spliceai ↗vcep_suppl_tables1_pmid_40580951cspec ↗
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_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 2 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PS3
supporting
review
Pathogenic
In an ATM VCEP supplementary variant table, the equivalent single-nucleotide representation c.4397G>C (p.Arg1466Pro) is listed as non-functional with high confidence. Under ATM VCEP rules, functional evidence showing failure to rescue an ATM-specific feature supports PS3 at supporting strength, although assay-level confirmation for this specific entry should be completed during final review.
Equivalent representation c.4397G>C corresponds to p.Arg1466ProSupplementary table classification: Non-functionalConfidence listed as High
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v4.1, which is below the ATM VCEP PM2_supporting threshold of less than or equal to 0.001%. It is also absent from gnomAD v2.1, supporting rarity in population databases.
Absent from gnomAD v4.1Absent from gnomAD v2.1ATM PM2 threshold <=0.001%
Assessed · not applied
· 11 not met · 0 not assessed
Pathogenic
PVS1
This variant is represented at the protein level as p.(Arg1466Pro) and does not fall within the ATM VCEP null-variant categories for PVS1.
PS1
This variant results in the missense change p.(Arg1466Pro).
PS4
This variant has been reported in ClinVar, but no case-control study or exact-variant enrichment data meeting the ATM VCEP PS4 threshold of p-value less than or equal to 0.05 and odds ratio, hazard ratio, or relative risk of at least 2, or lower 95% confidence interval of at least 1.5, were identified.
PM3
No confirmed in trans observations with a pathogenic or likely pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 is not met.
PP1
No segregation data were identified for this variant, so PP1 is not met.
PP3
SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the ATM splice PP3 threshold of at least 0.2.
Benign
BA1
This variant is absent from gnomAD v4.1 and does not meet the ATM BA1 threshold of greater than 0.5% population frequency.
BS1
This variant is absent from gnomAD v4.1 and does not meet the ATM BS1 threshold of greater than 0.05% population frequency.
BS3
No well-established study showing normal ATM function or rescue of radiosensitivity for this variant was identified.
BP2
No qualifying co-occurrence evidence in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual was identified, so BP2 is not met.
BP4
SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is within the ATM BP4 splice range of less than or equal to 0.1.
N/A · 15
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 (4 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links