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LYFE SCIENCES
Project: HERA
NM_000051.3:c.8161G>A
p.Asp2721Asn  ·  ATM
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Classification rationale
1

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.

clinvar ↗
2

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%.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
ClinVar evidence
02
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)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.957. BayesDel score = 0.0527644.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueD2721
Hotspots ↗