0%
EPCAMc.675G>ALikely benign
Print report
Variant interpretation report

EPCAM c.675G>A, p.(Leu225=)

NM_002354.3:c.675G>A NP_002345.2:p.(Leu225=) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign classification under the recorded framework.

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: 3
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Variant is extremely rare in population databases: gnomAD v2.1 AF = 0.00004% (1/251,376 alleles) and v4.1 AF = 0.000019% (3/1,613,358 alleles), well below the PM2 threshold of 0.1%.

Benign criteria applied · 3
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splicing alteration (max delta = 0.00, all sub-scores at 0.0), and the variant is synonymous with no predicted effect on protein sequence.

BP6Supporting
BP6 · supporting

ClinVar reports Likely benign classification by Ambry Genetics (criteria provided, single submitter), a reputable clinical laboratory. The classification is consistent with the synonymous nature of this variant.

BP7Supporting
BP7 · supporting

Synonymous variant (p.Leu225=) with SpliceAI max delta = 0.00 predicting no splice impact and no creation of a cryptic splice site. The variant lies in exon 7 (c.658-c.858) at position c.675, well within the exon body and not at a canonical splice consensus sequence.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 supporting + 3 supporting benign, which maps to Likely Benign.

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 / 1,613,358 alleles

gnomAD v4.1: 3 / 1,613,358 alleles. Recorded AF 1.85948e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.9781e-06; MAF= 0.00040%, 1/251376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79538e-06; MAF= 0.00088%, 1/113696 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Likely benign. ClinVar API review status: criteria provided, single submitter.

Applied · BP6 → ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 4 met · 16 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002354.3:c.675G>A is a synonymous variant (p.Leu225=) in exon 7 of EPCAM.

SpliceAI predicts no splicing impact (max delta = 0.00), satisfying BP4 and BP7 at supporting benign strength.

ClinVar lists this variant as Likely benign by Ambry Genetics, satisfying BP6 at supporting benign strength.

The variant is extremely rare in population databases: gnomAD v2.1 AF = 0.00004% (1/251,376) and v4.1 AF = 0.000019% (3/1,613,358), satisfying PM2 at supporting strength.

Overall, three supporting benign criteria (BP4, BP6, BP7) outweigh one supporting pathogenic criterion (PM2), resulting in a Likely Benign classification per generic ACMG/AMP 2015 combination rules.

Met · 4

PM2 SupportingVariant is extremely rare in population databases: gnomAD v2.1 AF = 0.00004% (1/251,376 alleles) and v4.1 AF = 0.000019% (3/1,613,358 alleles), well below the PM2 threshold of 0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1/251
  • 376 alleles (AF = 3.98e-6
  • 0.00040%)
  • gnomAD v4.1: 3/1
  • 613
  • 358 alleles (AF = 1.86e-6
  • 0.00019%)
  • Absent from gnomAD-Canada v1.0
  • No homozygotes observed in any population database
Still missing
  • Limited to exome data
  • genome sequencing coverage limited
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splicing alteration (max delta = 0.00, all sub-scores at 0.0), and the variant is synonymous with no predicted effect on protein sequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (DS_AG=0.0
  • DS_AL=0.0
  • DS_DG=0.0
  • DS_DL=0.0)
  • Synonymous variant with no predicted amino acid change
  • No cryptic splice site creation or donor/acceptor disruption
Still missing
  • Nucleotide conservation scores (phyloP
  • GERP) not available
Sources
spliceai ↗
BP6 SupportingClinVar reports Likely benign classification by Ambry Genetics (criteria provided, single submitter), a reputable clinical laboratory. The classification is consistent with the synonymous nature of this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 2624798: Likely benign (Ambry Genetics
  • SCV004092515)
  • Classification based on clinical testing with ACMG criteria provided
Still missing
  • Single submitter only
  • no expert panel review
Sources
clinvar ↗
BP7 SupportingSynonymous variant (p.Leu225=) with SpliceAI max delta = 0.00 predicting no splice impact and no creation of a cryptic splice site. The variant lies in exon 7 (c.658-c.858) at position c.675, well within the exon body and not at a canonical splice consensus sequence. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.Leu225= — no amino acid change
  • SpliceAI max delta = 0.00 — no predicted splicing alteration (all delta scores at 0.0)
  • Variant at c.675 within exon 7 (c.658-858)
  • not at canonical splice consensus (±1
  • 2)
Still missing
  • Nucleotide conservation data (phyloP
  • GERP) not available to confirm non-conservation component of BP7
Sources
spliceai ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo observation identified for this variant in the available evidence. Details ▾Hide ▴
Evidence considered
  • No de novo reports in ClinVar
  • literature
  • or case data
Still missing
  • No parental testing data available
PS3 No functional data available for this variant; OncoKB lists unknown oncogenic effect and no publications with variant-specific functional assays were identified. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • No publications with functional data for NM_002354.3:c.675G>A
Still missing
  • No experimental functional characterization of this variant exists
Sources
oncokb ↗
PS4 No case-control or enrichment data available; the variant is extremely rare in population databases (1-3 alleles) with no disease cohort observations. Details ▾Hide ▴
Evidence considered
  • Variant observed in 1/251
  • 376 alleles (gnomAD v2.1) and 3/1
  • 613
  • 358 alleles (gnomAD v4.1)
  • No case-control studies or enriched disease cohort observation
Still missing
  • No disease cohort frequency data available
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM1 No evidence that this synonymous nucleotide position lies within a critical functional domain specifically disrupted at the nucleotide level; SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 — no cryptic splice site creation or disruption
  • Not in a statistically significant mutational hotspot (cancerhotspots.org)
  • No REVEL/BayesDel scores to suggest nucleotide-level conservation
Still missing
  • Nucleotide-level conservation data (phyloP
  • GERP) not available
Sources
spliceai ↗
PM6 No de novo observation identified for this variant; PM6 requires confirmed de novo status with parental testing. Details ▾Hide ▴
Evidence considered
  • No de novo reports in ClinVar submissions
  • literature
  • or case data
Still missing
  • No parental testing data available
PP1 No segregation data available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation analysis identified
Still missing
  • No family pedigree or cosegregation data
PP3 No in silico tools predict a deleterious effect; SpliceAI max delta = 0.00, REVEL and BayesDel scores not available but synonymous variants are not expected to show pathogenic computational predictions. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 — no predicted splicing alteration
  • REVEL score not available (variant not in REVEL database)
  • BayesDel score not available
  • HCI prior probability not available for EPCAM
Still missing
  • REVEL and BayesDel not found for this variant
  • consistent with synonymous nature
Sources
spliceai ↗
PP4 No specific patient phenotype or clinical data provided for this variant; PP4 requires phenotype specificity supporting a diagnosis. Details ▾Hide ▴
Evidence considered
  • No proband phenotype or clinical features provided in case data
Still missing
  • No patient-specific clinical data available
PP5 ClinVar classification is Likely benign, not pathogenic; PP5 requires a reputable source to report the variant as pathogenic. The single ClinVar submission (Ambry Genetics, 1-star) classifies as Likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 2624798: Likely benign
  • criteria provided
  • single submitter (Ambry Genetics)
  • No expert panel or 3-star classification as pathogenic
Sources
clinvar ↗
BA1 Population frequency is extremely low: gnomAD v4.1 AF = 0.000019%, well below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF = 0.00040%
  • gnomAD v4.1 total AF = 0.00019%
  • Both far below 1% BA1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Population frequency is extremely low: gnomAD v4.1 AF = 0.000019%, well below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF = 0.00040%
  • gnomAD v4.1 total AF = 0.00019%
  • Both far below 0.3% BS1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 While this variant is observed in population databases (gnomAD), EPCAM-associated Lynch syndrome is an adult-onset disorder with reduced penetrance; observation in population controls does not exclude late-onset disease. BS2 is not met without confirmed healthy adult status with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
  • Variant observed in gnomAD (4 total alleles across v2.1 + v4.1) but Lynch syndrome has adult onset and reduced penetrance
  • No confirmed healthy adult data with documentation of full penetrance expected early
Still missing
  • Cannot confirm healthy adult status of gnomAD carriers
  • Adult-onset disease with reduced penetrance limits BS2 applicability
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional data demonstrating no deleterious effect for this variant; OncoKB lists unknown oncogenic effect with no publications supporting a benign functional impact. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • No publications with functional data for NM_002354.3:c.675G>A
Still missing
  • No experimental functional characterization of this variant exists
Sources
oncokb ↗
BS4 No segregation data available demonstrating lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
  • No family studies or non-segregation data identified
Still missing
  • No family pedigree or cosegregation data
BP2 No phase data available; BP2 requires observation in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
  • No phase information available for this variant
Still missing
  • No co-occurrence or phase data with known pathogenic EPCAM variants
BP5 No evidence of an alternate molecular basis for disease in a case carrying this variant. Details ▾Hide ▴
Evidence considered
  • No case identified where this variant was found alongside a confirmed alternate genetic cause
Still missing
  • No case-level data with alternate molecular diagnosis
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (p.Leu225=) with no predicted null effect on protein; PVS1 is not applicable to silent variants. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution at c.675G>A produces no amino acid change (p.Leu225=)
  • Variant does not fall into PVS1 null-variant buckets (nonsense
  • frameshift
  • canonical splice)
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ASynonymous variant with no amino acid change; PS1 requires the same amino acid change as an established pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.Leu225= — no amino acid substitution to compare
PM5 N/ASynonymous variant with no amino acid change; PM5 requires a different amino acid change at the same residue as an established pathogenic missense variant. Details ▾Hide ▴
Evidence considered
  • No residue-level amino acid change — PM5 semantics cannot be applied
  • pm5_candidates confirmation: not eligible for classic same-residue search
Sources
pm5_candidates
PP2 N/ASynonymous variant, not missense; PP2 is specific to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • Variant is synonymous (p.Leu225=)
  • not a missense change
BP1 N/ASynonymous variant, not missense; BP1 applies to missense variants in genes where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
  • Variant is synonymous (p.Leu225=)
  • not a missense change
PS5 N/ASynonymous variant; PS5 is applicable only to missense variants at a residue where a different pathogenic missense change is established. Details ▾Hide ▴
Evidence considered
  • Synonymous variant produces no amino acid change
  • PS5 criterion is missense-specific

Identifiers

Gene
EPCAM
Transcript
NM_002354.3
Coding (HGVS c.)
NM_002354.3:c.675G>A
Protein (HGVS p.)
NP_002345.2:p.(Leu225=)
GRCh38
chr2:47379786 G>A
GRCh37
chr2:47606925 G>A
ClinVar
2624798

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 / 1,613,358 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 1 / 251,376 alleles AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,613,358 alleles · 0 hom · FAF 6.8e-07
European (non-Finnish)3 / 1,179,868 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.

gnomAD v2.1

AF 4e-06 · 1 / 251,376 alleles · 0 hom
European (non-Finnish)1 / 113,696 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= 1.85948e-06; MAF= 0.00019%, 3/1613358 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54266e-06; MAF= 0.00025%, 3/1179868 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.9781e-06; MAF= 0.00040%, 1/251376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79538e-06; MAF= 0.00088%, 1/113696 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +13 bp
0.000
SpliceAI acceptor gainat +112 bp
0.000
SpliceAI donor lossat -237 bp
0.000
SpliceAI donor gainat -11 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splicing alteration (max delta = 0.00, all sub-scores at 0.0), and the variant is synonymous with no predicted effect on protein sequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (DS_AG=0.0
  • DS_AL=0.0
  • DS_DG=0.0
  • DS_DL=0.0)
  • Synonymous variant with no predicted amino acid change
  • No cryptic splice site creation or donor/acceptor disruption
Still missing
  • Nucleotide conservation scores (phyloP
  • GERP) not available
Sources
spliceai ↗
BP7 SupportingSynonymous variant (p.Leu225=) with SpliceAI max delta = 0.00 predicting no splice impact and no creation of a cryptic splice site. The variant lies in exon 7 (c.658-c.858) at position c.675, well within the exon body and not at a canonical splice consensus sequence. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.Leu225= — no amino acid change
  • SpliceAI max delta = 0.00 — no predicted splicing alteration (all delta scores at 0.0)
  • Variant at c.675 within exon 7 (c.658-858)
  • not at canonical splice consensus (±1
  • 2)
Still missing
  • Nucleotide conservation data (phyloP
  • GERP) not available to confirm non-conservation component of BP7
Sources
spliceai ↗
PP3 No in silico tools predict a deleterious effect; SpliceAI max delta = 0.00, REVEL and BayesDel scores not available but synonymous variants are not expected to show pathogenic computational predictions. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 — no predicted splicing alteration
  • REVEL score not available (variant not in REVEL database)
  • BayesDel score not available
  • HCI prior probability not available for EPCAM
Still missing
  • REVEL and BayesDel not found for this variant
  • consistent with synonymous nature
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. A general clinical guidance document; does not discuss or cite the EPCAM c.675G>A variant.
    Does not name this variant
    PMID 25394175 ↗

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

gnomAD v4.1 3 / 1,613,358 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
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= 1.85948e-06; MAF= 0.00019%, 3/1613358 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54266e-06; MAF= 0.00025%, 3/1179868 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.9781e-06; MAF= 0.00040%, 1/251376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79538e-06; MAF= 0.00088%, 1/113696 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 2624798)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.