Starting

Initialising…

EPCAM

Final classification

VUS

EPCAM c.457A>G · p.Arg153Gly

EPCAM

Gene

EPCAM

Transcript

NM_002354.3

HGVS · transcript:coding

NM_002354.3:c.457A>G

Consequence

N/A

GRCh38

chr2:47375265 A>G

GRCh37

chr2:47602404 A>G

Basis Generic ACMG/AMP 2015 final classification combination rules were used because no explicit official or custom gene-specific final-classification framework was available. ▾

Generic ACMG/AMP 2015 final classification combination rules were used because no explicit official or custom gene-specific final-classification framework was available.

Classification rationale

PM2 VUS

EPCAM c.457A>G

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.¹ 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.² 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.³

PM2 → VUS

1 cosmicclinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗prefetch

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

Benign evidence

—

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= 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.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,611,766
0 hom · FAF 6.8e-05%

European (non-Finnish)

3 / 1,178,080

0.00025%

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

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 = 0.01).

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; COSV55394328, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

Hotspots ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots