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LYFE SCIENCES
Project: HERA
NM_000051.3:c.5681_5682del
p.Glu1894AlafsTer9  ·  ATM
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Classification rationale
1

The ATM NM_000051.3:c.5681_5682del (NP_000042.3:p.(Glu1894AlafsTer9); p.(E1894Afs*9)) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.

clinvar ↗ cspec ↗
2

This variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06; 0 homozygotes), which is below the ATM PM2_Supporting threshold of 0.001% and well below the BS1 and BA1 thresholds.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

The variant is a frameshift predicted to truncate ATM at codon 1894, and under the ATM VCEP framework this supports PVS1 because loss of function is an established disease mechanism for ATM; the ATM-specific PM5 truncation rule also applies because the premature termination is upstream of p.Arg3047.

cspec ↗
4

SpliceAI predicts no significant splice effect for this variant (maximum delta score 0.14), which is below the ATM PP3 splice threshold of 0.2 and above the BP4 benign splice threshold of 0.1.

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
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.85994e-06; MAF= 0.00019%, 3/1612956 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60149e-05; MAF= 0.00160%, 1/62442 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 407525)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE1894
Hotspots ↗