Classification rationale

PM2 VUS

EPCAM c.294C>G

The EPCAM c.294C>G (p.Asp98Glu; p.D98E) variant has not been identified in a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance from one clinical laboratory.¹ This variant is rare in population databases, with allele frequencies of 0.00040% in gnomAD v2.1 and 0.00037% in gnomAD v4.1, both below the 0.1% PM2 threshold, and no homozygotes were observed.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03.³

PM2 → VUS

1 hotspots ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

Gene diagram · NM_002354.3 · variants mapped to exon structure

EPCAM NM_002354.3

Fetching transcript structure from UCSC…

Applied criteria · 1 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

This variant is present in gnomAD v4.1 (AF= 3.71728e-06; MAF= 0.00037%, 6/1614082 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08463e-06; MAF= 0.00051%, 6/1180026 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.9764e-06; MAF= 0.00040%, 1/251484 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79059e-06; MAF= 0.00088%, 1/113758 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00037% · 6 / 1,614,082
0 hom · FAF 0.00018%

European (non-Finnish)

6 / 1,180,026

0.00051%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,484
0 hom

European (non-Finnish)

1 / 113,758

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional 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 ↗

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; COSV55392660, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots