NM_002354.3:c.294C>G

EPCAM · NP_002345.2:p.(Asp98Glu) · NM_002354.3

GRCh37: chr2:47601056 C>G · GRCh38: chr2:47373917 C>G

Gene: EPCAM Transcript: NM_002354.3

Final call

VUS

PM2_Moderate

Variant details

Gene

EPCAM

Transcript

NM_002354.3

Protein

NP_002345.2:p.(Asp98Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No pathogenic or likely pathogenic variant producing the same amino acid substitution was identified in the available evidence, so PS1 was not applied.	clinvar
PS2	Not assessed	No confirmed de novo occurrence data with verified maternity and paternity were identified, so PS2 was not assessed.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not applied.	oncokb
PS4	Not assessed	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.	clinvar
PM1	Not met	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.	hotspots
PM2	Met	Population frequency is below the default PM2 threshold of 0.1% in both gnomAD v2.1 (0.00040%, 1/251484 alleles) and gnomAD v4.1 (0.00037%, 6/1614082 alleles), with no homozygotes observed, which supports rarity consistent with PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant for a recessive disorder, so PM3 was not assessed.
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 is not applicable.
PM5	Not assessed	No pathogenic missense variant at the same codon was identified in the available evidence, so PM5 was not applied.	clinvar
PM6	Not assessed	No assumed de novo data without confirmed parentage were identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified to show cosegregation with disease in affected family members, so PP1 was not applied.
PP2	Not assessed	Available evidence does not establish that missense variation is a common disease mechanism for EPCAM, so PP2 was not applied.	pvs1_gene_context
PP3	Not assessed	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.	spliceai
PP4	Not assessed	No phenotype or tumor profile data specific enough to support a highly specific EPCAM-related presentation were identified, so PP4 was not applied.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults in a manner sufficient to support BS2, so BS2 was not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not applied.	oncokb
BS4	Not assessed	No nonsegregation data were identified in affected families, so BS4 was not assessed.
BP1	Not assessed	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.	pvs1_gene_context
BP2	Not assessed	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.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable.
BP4	Not assessed	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.	spliceai
BP5	Not assessed	No alternate molecular explanation for the observed phenotype was identified, so BP5 was not assessed.
BP6	Not met	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.	clinvar
BP7	N/A	This variant is a missense substitution rather than a synonymous or intronic change, so BP7 is not applicable.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.