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
ATM
Final classification
VUS
ATM c.8161G>A · p.Asp2721Asn
ATM
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 ↗
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 3 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.
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