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EPCAMc.457A>GUncertain significance
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Variant interpretation report

EPCAM c.457A>G, p.(Arg153Gly)

NM_002354.3:c.457A>G NP_002345.2:p.(Arg153Gly) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About EPCAM

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Met
PM2

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,611,766 alleles

gnomAD v4.1: 3 / 1,611,766 alleles. Recorded AF 1.86131e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 6 not met · 17 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

Met · 1

PM2 MetPopulation 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 AF 1.86131e-06; 3/1611766 alleles; NFE AF 2.54652e-06
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 6 · evaluated, threshold not reached

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. Available evidence does not support PS4. Details ▾Hide ▴
Evidence considered
  • COSMIC COSV55394328 somatic count 1
  • ClinVar VUS, single submitter
Still missing
  • No case-control enrichment data were identified.
  • No series of affected probands attributable to this variant were identified.
Sources
cosmicclinvar ↗
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. Available evidence does not support PM1. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no hotspot row found for EPCAM R153
Still missing
  • No domain-specific pathogenic enrichment data were identified.
Sources
hotspots ↗
PP3 Available computational evidence does not provide concordant support for a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the REVEL score is 0.363, which does not support a clear damaging prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.01
  • REVEL 0.363
Still missing
  • No additional concordant deleterious computational evidence was identified.
Sources
spliceai ↗prefetch
BA1 Population frequency does not meet a stand-alone benign threshold. The highest observed frequency is 0.00025% in gnomAD v4.1, which is below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 NFE AF 0.00025%
Sources
gnomad_v4 ↗
BS1 Population frequency is not greater than expected for a benign variant under the default threshold. The highest observed frequency is 0.00025% in gnomAD v4.1, which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 NFE AF 0.00025%
Sources
gnomad_v4 ↗
BP4 Available computational evidence is insufficient to support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the REVEL score of 0.363 is not low enough to provide concordant benign computational evidence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.01
  • REVEL 0.363
Still missing
  • No additional concordant benign computational evidence was identified.
Sources
spliceai ↗prefetch

Not assessed · 17 · no assessment recorded

PS1 No evidence was identified that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant. PS1 cannot be applied from the available data. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS entry only
Still missing
  • No established pathogenic variant with the same amino acid change was identified.
Sources
clinvar ↗
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No de novo case data were identified.
PS3 No well-established functional studies demonstrating a damaging effect of p.Arg153Gly were identified. PS3 cannot be applied from the available evidence. Details ▾Hide ▴
Still missing
  • No validated functional assay data were identified.
PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context. PM3 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No phase data were identified.
  • No recessive case data were identified.
PM5 No evidence was identified for a different pathogenic missense change at codon 153 that would support PM5. PM5 cannot be applied from the available data. Details ▾Hide ▴
Evidence considered
  • ClinVar contains this variant as VUS only
Still missing
  • No established pathogenic alternate missense change at the same residue was identified.
Sources
clinvar ↗
PM6 No presumed de novo occurrence was identified for this variant. PM6 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No de novo case reports were identified.
PP1 No segregation data were identified for this variant. PP1 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No family segregation studies were identified.
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. PP2 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No missense constraint or mechanism-specific EPCAM data were identified.
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. PP4 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No phenotype-specific case information was identified.
PP5 ClinVar lists this variant as uncertain significance from a single submitter, which does not provide a sufficiently established pathogenic assertion for PP5. PP5 is not applied. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS, criteria provided, single submitter
Still missing
  • No reputable pathogenic classification without accessible supporting evidence was identified.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adults at a count sufficient for BS2. Although no homozygotes are reported in gnomAD v4.1, these data do not support BS2. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 homozygotes 0
Still missing
  • No well-powered observations in unaffected individuals were identified.
Sources
gnomad_v4 ↗
BS3 No well-established functional studies demonstrating a benign effect of p.Arg153Gly were identified. BS3 cannot be applied from the available evidence. Details ▾Hide ▴
Still missing
  • No validated benign functional assay data were identified.
BS4 No segregation studies were identified showing lack of segregation with disease. BS4 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No family non-segregation data were identified.
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. BP1 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No gene-specific missense-versus-truncating mechanism data were identified.
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. BP2 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No phase data were identified.
BP5 No alternate molecular explanation for the observed disease phenotype was identified that would support BP5. BP5 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • No case-level alternate diagnosis data were identified.
BP6 No reputable benign classification without available supporting evidence was identified. ClinVar lists this variant as uncertain significance, so BP6 is not applied. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS, single submitter
Still missing
  • No reputable benign assertion was identified.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, NM_002354.3:c.457A>G (p.Arg153Gly), and not a predicted null variant. Available evidence does not support use of a loss-of-function criterion for this change. Details ▾Hide ▴
Evidence considered
  • Missense consequence p.Arg153Gly
Sources
prefetch
PM4 N/AThis variant is a single amino acid substitution and does not change protein length. PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense consequence p.Arg153Gly
Sources
prefetch
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region. BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense consequence p.Arg153Gly
Sources
prefetch
BP7 N/AThis is not a synonymous or intronic splice-region variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense consequence p.Arg153Gly
Sources
prefetch

Identifiers

Gene
EPCAM
Transcript
NM_002354.3
Coding (HGVS c.)
NM_002354.3:c.457A>G
Protein (HGVS p.)
NP_002345.2:p.(Arg153Gly)
GRCh38
chr2:47375265 A>G
GRCh37
chr2:47602404 A>G

Gene diagram

Every interpreted variant in EPCAM, mapped onto the exon structure of NM_002354.3. Select a row to find it on the plot.

EPCAMNM_002354.3
Fetching transcript structure from UCSC…
gnomAD v4.1 3 / 1,611,766 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,611,766 alleles · 0 hom · FAF 6.8e-07
European (non-Finnish)3 / 1,178,080 2.5e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Available computational evidence does not provide concordant support for a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the REVEL score is 0.363, which does not support a clear damaging prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.01
  • REVEL 0.363
Still missing
  • No additional concordant deleterious computational evidence was identified.
Sources
spliceai ↗prefetch
BP4 Available computational evidence is insufficient to support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the REVEL score of 0.363 is not low enough to provide concordant benign computational evidence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.01
  • REVEL 0.363
Still missing
  • No additional concordant benign computational evidence was identified.
Sources
spliceai ↗prefetch
BP7 N/AThis is not a synonymous or intronic splice-region variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense consequence p.Arg153Gly
Sources
prefetch

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 3 / 1,611,766 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

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

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

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.

Somatic

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

This variant does not lie in a statistically significant hotspot.