The ATM c.8161G>A (p.Asp2721Asn; p.D2721N) variant has been observed in somatic cancers (COSMIC COSV53771356, n=10) and has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel classified it as Likely Pathogenic.1 This variant is absent from both gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the ATM PM2_Supporting frequency threshold of <=0.001%.2 Available computational evidence supports a damaging missense effect: REVEL is 0.957, above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644; a VCEP-linked supplementary table scored the variant as non-functional with medium-high confidence; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.07.3
Final classification
VUS
PM2PP3PP5
ATM
c.8161G>A
p.Asp2721Asn
This variant
The ATM c.8161G>A (p.Asp2721Asn; p.D2721N) variant has been observed in somatic cancers (COSMIC COSV53771356, n=10) and has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel classified it as Likely Pathogenic.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3PP5
VUS
ATM c.8161G>A
PM2 + PP3 + PP5
→
VUS
3
revelbayesdelspliceai ↗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 · 3 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed frequency is therefore 0, which is below the ATM PM2_Supporting threshold of <=0.001%.
Absent from gnomAD v4.1Absent from gnomAD v2.1ATM PM2 threshold is <=0.001% in gnomAD v4
PP3
supporting
Pathogenic
Available computational evidence supports a damaging missense effect. REVEL is 0.957, which is above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644, also favoring deleteriousness. SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, supporting interpretation as a missense effect rather than a splice effect.
REVEL 0.957BayesDel 0.0527644SpliceAI max delta 0.07
Assessed · not applied
· 3 not met · 7 not assessed
Pathogenic
PS1
No evidence was identified showing that this variant produces the same amino acid change as an established ATM pathogenic or likely pathogenic variant, and SpliceAI does not suggest an alternative splice-based PS1 scenario for this substitution.
PS3
No ATM VCEP-approved functional study was identified showing that this variant fails to rescue an ATM-specific function or radiosensitivity.
PS4
This variant has been reported in ClinVar and in somatic cancer databases, but no case-control study or other enrichment data meeting the ATM PS4 threshold were identified.
PM3
No evidence was identified showing this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia, so PM3 cannot be assigned from the available evidence.
PP1
No segregation data were identified showing this variant tracking with ataxia-telangiectasia in affected relatives, so PP1 cannot be assigned.
Benign
BA1
This variant is absent from gnomAD v4.1, so its frequency is 0 and does not meet the ATM BA1 threshold of >0.5%.
BS1
This variant is absent from gnomAD v4.1, so its frequency is 0 and does not meet the ATM BS1 threshold of >0.05%.
BS3
No ATM VCEP-approved functional study was identified showing rescue of both an ATM-specific feature and radiosensitivity, or rescue of either one alone, for this variant.
BP2
No evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected non-A-T individual, so BP2 cannot be assigned.
BP4
BP4 is not met because the missense predictor threshold is not satisfied: REVEL is 0.957, which is above the ATM BP4 cutoff of <=0.249.
N/A · 15
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · 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) and as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 1054111)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.957. BayesDel score = 0.0527644.
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; COSV53771356, n = 10 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 10 PMIDs not cited in assessment
21665257 ↗
Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
29906526 ↗
PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects.
CLINVAR
24418350 ↗
EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR