Variant classification summary

NM_002354.3:c.675G>A

EPCAM · NP_002345.2:p.(Leu225=) · NM_002354.3

GRCh37: chr2:47606925 G>A · GRCh38: chr2:47379786 G>A

Gene: EPCAM Transcript: NM_002354.3

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

EPCAM

Transcript

NM_002354.3

Protein

NP_002345.2:p.(Leu225=)

gnomAD AF

1.859475702230999e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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

3

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

4

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.

5

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	Synonymous variant (p.Leu225=) with no predicted null effect on protein; PVS1 is not applicable to silent variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Synonymous variant with no amino acid change; PS1 requires the same amino acid change as an established pathogenic variant.
PS2	Not met	No de novo observation identified for this variant in the available evidence.
PS3	Not met	No functional data available for this variant; OncoKB lists unknown oncogenic effect and no publications with variant-specific functional assays were identified.	oncokb
PS4	Not met	No case-control or enrichment data available; the variant is extremely rare in population databases (1-3 alleles) with no disease cohort observations.	gnomad_v2 gnomad_v4
PS5	N/A	Synonymous variant; PS5 is applicable only to missense variants at a residue where a different pathogenic missense change is established.
PM1	Not met	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).	spliceai
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	Synonymous variant with no amino acid change; PM5 requires a different amino acid change at the same residue as an established pathogenic missense variant.	pm5_candidates
PM6	Not met	No de novo observation identified for this variant; PM6 requires confirmed de novo status with parental testing.
PP1	Not met	No segregation data available for this variant.
PP2	N/A	Synonymous variant, not missense; PP2 is specific to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	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.	spliceai
PP4	Not met	No specific patient phenotype or clinical data provided for this variant; PP4 requires phenotype specificity supporting a diagnosis.
PP5	Not met	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.	clinvar
BA1	Not met	Population frequency is extremely low: gnomAD v4.1 AF = 0.000019%, well below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency is extremely low: gnomAD v4.1 AF = 0.000019%, well below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	No functional data demonstrating no deleterious effect for this variant; OncoKB lists unknown oncogenic effect with no publications supporting a benign functional impact.	oncokb
BS4	Not met	No segregation data available demonstrating lack of cosegregation with disease.
BP1	N/A	Synonymous variant, not missense; BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2	Not met	No phase data available; BP2 requires observation in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP4	Met	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
BP5	Not met	No evidence of an alternate molecular basis for disease in a case carrying this variant.
BP6	Met	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
BP7	Met	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.	spliceai

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