Classification rationale

PM2 BP4BP6BP7 Likely Benign

EPCAM c.675G>A

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.¹ ClinVar lists this variant as Likely benign by Ambry Genetics, satisfying BP6 at supporting benign strength.² 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.³ 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.⁴

PM2 + BP4 + BP6 + BP7 → Likely Benign

1 spliceai ↗

2 clinvar ↗

3 gnomad_v2 ↗gnomad_v4 ↗

4 generic_acmg_combination_rules

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

EPCAM NM_002354.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 16 assessed

Applied · 4

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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%.

gnomAD v2.1: 1/251376 alleles (AF = 3.98e-60.00040%)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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.

SpliceAI max delta = 0.00 (DS_AG=0.0DS_AL=0.0DS_DG=0.0

spliceai ↗

✓

BP6 supporting Benign

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.

ClinVar Variation ID 2624798: Likely benign (Ambry GeneticsSCV004092515)Classification based on clinical testing with ACMG criteria provided

clinvar ↗

✓

BP7 supporting Benign

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.

Synonymous variant p.Leu225= — no amino acid changeSpliceAI max delta = 0.00 — no predicted splicing alteration (all delta scores at 0.0)Variant at c.675 within exon 7 (c.658-858)

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo observation identified for this variant in the available evidence.

PS3 No functional data available for this variant; OncoKB lists unknown oncogenic effect and no publications with variant-specific functional assays were identified.

PS4 No case-control or enrichment data available; the variant is extremely rare in population databases (1-3 alleles) with no disease cohort observations.

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).

PM6 No de novo observation identified for this variant; PM6 requires confirmed de novo status with parental testing.

PP1 No segregation data available for this variant.

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.

PP4 No specific patient phenotype or clinical data provided for this variant; PP4 requires phenotype specificity supporting a diagnosis.

PP5 ClinVar classification is Likely benign, not pathogenic; PP5 requires a reputable source to report the variant as pathogenic.

Benign

BA1 Population frequency is extremely low: gnomAD v4.1 AF = 0.000019%, well below the BA1 threshold of 1%.

BS1 Population frequency is extremely low: gnomAD v4.1 AF = 0.000019%, well below the BS1 threshold of 0.3%.

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.

BS3 No functional data demonstrating no deleterious effect for this variant; OncoKB lists unknown oncogenic effect with no publications supporting a benign functional impact.

BS4 No segregation data available demonstrating lack of cosegregation with disease.

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.

BP5 No evidence of an alternate molecular basis for disease in a case carrying this variant.

N/A · 5 PVS1 · PS1 · PM5 · PP2 · BP1

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

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.

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).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,613,358
0 hom · FAF 6.8e-05%

European (non-Finnish)

3 / 1,179,868

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

0.0004% · 1 / 251,376
0 hom

European (non-Finnish)

1 / 113,696

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

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

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

25394175 ↗ 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. CLINVAR