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LYFE SCIENCES
Project: HERA
NM_002354.3:c.457A>G
p.Arg153Gly  ·  EPCAM
ACMG/AMP
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Legacy Engine
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Classification rationale
1

The EPCAM c.457A>G (p.Arg153Gly) variant has been observed once in somatic cancers in COSMIC (COSV55394328) and has been reported in ClinVar as a variant of uncertain significance with one clinical laboratory submission.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,611,766 alleles (AF 0.00019%), with a highest observed population frequency of 0.00025% in European non-Finnish individuals, which is below the 0.1% PM2 threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

Available computational evidence does not support a splice effect, with a SpliceAI maximum delta score of 0.01, and the REVEL score of 0.363 does not provide concordant evidence for either a pathogenic or benign missense effect.

spliceai ↗
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
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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= 1.86131e-06; MAF= 0.00019%, 3/1611766 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54652e-06; MAF= 0.00025%, 3/1178080 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: EPCAM, a transmembrane glycoprotein, is overexpressed in various cancer types.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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; COSV55394328, n = 1 times).
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR153
Hotspots ↗