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

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

EPCAM NM_002354.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 review Pathogenic

Population frequency is very low. 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 highest observed subpopulation frequency 0.00025% in European non-Finnish individuals; this is below the 0.1% PM2 threshold.

gnomAD v2.1 absentgnomAD v4.1 AF 1.86131e-06; 3/1611766 alleles; NFE AF 2.54652e-06

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 6 not met · 17 not assessed

Pathogenic

PS1 No evidence was identified that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 No well-established functional studies demonstrating a damaging effect of p.Arg153Gly were identified.

PS4 This variant has been observed once in COSMIC and is reported in ClinVar as a variant of uncertain significance from a single clinical laboratory, but these data do not demonstrate enrichment in affected individuals over controls.

PM1 This variant does not lie in a statistically significant hotspot, and no evidence was identified that Arg153 is located in a well-established critical functional domain without benign variation.

PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context.

PM5 No evidence was identified for a different pathogenic missense change at codon 153 that would support PM5.

PM6 No presumed de novo occurrence was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 No gene-specific evidence was identified showing that pathogenic EPCAM missense variation is a common disease mechanism and that the gene has a low rate of benign missense variation.

PP3 Available computational evidence does not provide concordant support for a deleterious effect.

PP4 No phenotype information was identified showing a highly specific clinical presentation or family history attributable to EPCAM-related disease in a way that supports this variant.

PP5 ClinVar lists this variant as uncertain significance from a single submitter, which does not provide a sufficiently established pathogenic assertion for PP5.

Benign

BA1 Population frequency does not meet a stand-alone benign threshold.

BS1 Population frequency is not greater than expected for a benign variant under the default threshold.

BS2 No evidence was identified showing this variant in healthy adults at a count sufficient for BS2.

BS3 No well-established functional studies demonstrating a benign effect of p.Arg153Gly were identified.

BS4 No segregation studies were identified showing lack of segregation with disease.

BP1 No gene-specific evidence was identified showing that truncating variants predominate as the established disease mechanism for EPCAM in a way that would support a benign interpretation of this missense change.

BP2 No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.

BP4 Available computational evidence is insufficient to support a benign effect.

BP5 No alternate molecular explanation for the observed disease phenotype was identified that would support BP5.

BP6 No reputable benign classification without available supporting evidence was identified.

N/A · 4 PVS1 · PM4 · BP3 · BP7

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

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