EPCAM c.294C&gt;G , p.(Asp98Glu)

Not met · 5 · evaluated, threshold not reached

PM1 This variant has not been identified in a statistically significant hotspot or other established critical functional region without benign variation in the available evidence, so PM1 is not met. Details ▾Hide ▴

Evidence considered

Cancer Hotspots review did not identify a hotspot row for EPCAM residue D98.

Still missing

If gene-specific domain data become available
regional interpretation could be revisited.

Sources

hotspots ↗

PP5 ClinVar reports this variant as uncertain significance with no assertion criteria provided, which does not support a pathogenic classification by a reputable source, so PP5 is not met. Details ▾Hide ▴

Evidence considered

ClinVar classification: Uncertain significance
review status: no assertion criteria provided.

Sources

BA1 Population frequency is below the BA1 threshold of 1% in both gnomAD v2.1 (0.00040%) and gnomAD v4.1 (0.00037%), so BA1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF 0.00040%.
gnomAD v4.1 AF 0.00037%.

Sources

BS1 Population frequency is below the default BS1 threshold of 0.3% in both gnomAD v2.1 (0.00040%) and gnomAD v4.1 (0.00037%), so BS1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF 0.00040%.
gnomAD v4.1 AF 0.00037%.

Sources

BP6 No reputable source classified this variant as benign or likely benign in the available evidence; ClinVar lists it as uncertain significance, so BP6 is not met. Details ▾Hide ▴

Evidence considered

ClinVar classification: Uncertain significance.

Sources

Not assessed · 18 · no assessment recorded

PS1 No pathogenic or likely pathogenic variant producing the same amino acid substitution was identified in the available evidence, so PS1 was not applied. Details ▾Hide ▴

Evidence considered

ClinVar lists this variant as uncertain significance with one clinical laboratory submission.

Still missing

A broader residue-level review beyond the currently retrieved sources would be needed to exclude all possible same-amino-acid pathogenic substitutions.

Sources

PS2 No confirmed de novo occurrence data with verified maternity and paternity were identified, so PS2 was not assessed. Details ▾Hide ▴

Still missing

Parental testing and de novo confirmation data were not available.

PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not applied. Details ▾Hide ▴

Evidence considered

OncoKB has not reviewed this specific variant and provides no variant-level biological effect.

Still missing

Validated functional assay data for EPCAM p.(Asp98Glu) were not available.

Sources

oncokb ↗

PS4 No case-control or enrichment data showing that this variant is more frequent in affected individuals than in controls were identified, so PS4 was not applied. Details ▾Hide ▴

Evidence considered

ClinVar contains a single uncertain-significance submission and no aggregate prevalence evidence.

Still missing

Affected-case counts and controlled comparison data were not available.

Sources

PM3 No evidence was identified showing this variant in trans with a pathogenic variant for a recessive disorder, so PM3 was not assessed. Details ▾Hide ▴

Still missing

Phase information and recessive-case data were not available.

PM5 No pathogenic missense variant at the same codon was identified in the available evidence, so PM5 was not applied. Details ▾Hide ▴

Evidence considered

Available ClinVar evidence identifies this variant but does not provide a pathogenic codon-matched comparator.

Still missing

A broader codon-specific review would be needed to exclude all possible pathogenic substitutions at residue 98.

Sources

PM6 No assumed de novo data without confirmed parentage were identified, so PM6 was not assessed. Details ▾Hide ▴

Still missing

Parental testing data were not available.

PP1 No segregation data were identified to show cosegregation with disease in affected family members, so PP1 was not applied. Details ▾Hide ▴

Still missing

Family segregation studies were not available.

PP2 Available evidence does not establish that missense variation is a common disease mechanism for EPCAM, so PP2 was not applied. Details ▾Hide ▴

Evidence considered

Gene-level evidence supports loss of function as a disease mechanism
but not a predominant missense mechanism.

Still missing

Gene-specific missense mechanism and constraint evidence were not available.

Sources

pvs1_gene_context

PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.03), and no validated multi-tool computational framework supporting a damaging missense effect was identified in the available evidence, so PP3 was not applied. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.03.

Still missing

Additional validated protein-impact prediction framework data were not available in the cited sources.

Sources

PP4 No phenotype or tumor profile data specific enough to support a highly specific EPCAM-related presentation were identified, so PP4 was not applied. Details ▾Hide ▴

Still missing

Clinical phenotype
family history
and syndrome-specific features were not available.

BS2 No evidence was identified showing this variant in healthy adults in a manner sufficient to support BS2, so BS2 was not assessed. Details ▾Hide ▴

Evidence considered

No homozygotes were observed in gnomAD
but this alone is insufficient for BS2.

Still missing

Well-phenotyped unaffected-carrier data were not available.

Sources

BS3 No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not applied. Details ▾Hide ▴

Evidence considered

OncoKB provides no variant-level functional assessment for this variant.

Still missing

Validated benign functional assay data were not available.

Sources

oncokb ↗

BS4 No nonsegregation data were identified in affected families, so BS4 was not assessed. Details ▾Hide ▴

Still missing

Family-based segregation studies were not available.

BP1 Although EPCAM loss of function is an established disease mechanism, available evidence does not show that missense variation is sufficiently uncommon or typically benign in this gene to support BP1, so BP1 was not applied. Details ▾Hide ▴

Evidence considered

Gene-level evidence supports loss of function as a disease mechanism.

Still missing

Gene-specific evidence about the distribution and significance of missense variants in EPCAM was not available.

Sources

pvs1_gene_context

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant condition, or in cis with another pathogenic variant, so BP2 was not assessed. Details ▾Hide ▴

Still missing

Phase and genotype-context data were not available.

BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.03), but no validated computational framework was identified in the cited sources to support a benign missense interpretation, so BP4 was not applied. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.03.

Still missing

Additional validated protein-impact prediction evidence was not available in the cited sources.

Sources

BP5 No alternate molecular explanation for the observed phenotype was identified, so BP5 was not assessed. Details ▾Hide ▴

Still missing

Detailed phenotype and alternate-cause data were not available.

Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis missense variant does not fall within the generic PVS1 null-variant categories, and the generic PVS1 assessment states that PVS1 should not be applied for this change. Details ▾Hide ▴

Evidence considered

EPCAM loss of function is an established disease mechanism at the gene level.
NM_002354.3:c.294C>G results in p.(Asp98Glu)
not a nonsense
frameshift
or canonical +/-1
2 splice variant.

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴

Evidence considered

Variant consequence is p.(Asp98Glu).

BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴

Evidence considered

Variant consequence is a single amino acid substitution.

BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic change, so BP7 is not applicable. Details ▾Hide ▴

Evidence considered

Variant consequence is p.(Asp98Glu)
SpliceAI was reviewed only for possible splice impact.

Sources

Identifiers

Gene: EPCAM
Transcript: NM_002354.3
Coding (HGVS c.): NM_002354.3:c.294C>G
Protein (HGVS p.): NP_002345.2:p.(Asp98Glu)
GRCh38: chr2:47373917 C>G
GRCh37: chr2:47601056 C>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…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in EPCAM — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 6 / 1,614,082 alleles AF 3.72e-06 · 0 homozygotes · FAF 1.83e-06

gnomAD v2.1 1 / 251,484 alleles AF 3.98e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 3.7e-06 · 6 / 1,614,082 alleles · 0 hom · FAF 1.8e-06

European (non-Finnish)6 / 1,180,026

5.1e-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.

gnomAD v2.1

AF 4e-06 · 1 / 251,484 alleles · 0 hom

European (non-Finnish)1 / 113,758

8.8e-06

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD v2.1

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score = 0.03.

Still missing

Additional validated protein-impact prediction framework data were not available in the cited sources.

Sources

Evidence considered

SpliceAI max delta score = 0.03.

Still missing

Additional validated protein-impact prediction evidence was not available in the cited sources.

Sources

BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic change, so BP7 is not applicable. Details ▾Hide ▴

Evidence considered

Variant consequence is p.(Asp98Glu)
SpliceAI was reviewed only for possible splice impact.

Sources