NM_002354.3:c.457A>G

EPCAM · NP_002345.2:p.(Arg153Gly) · NM_002354.3

GRCh37: chr2:47602404 A>G · GRCh38: chr2:47375265 A>G

Gene: EPCAM Transcript: NM_002354.3

Final call

VUS

PM2

Variant details

Gene

EPCAM

Transcript

NM_002354.3

Protein

NP_002345.2:p.(Arg153Gly)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The EPCAM c.457A>G (p.Arg153Gly) variant has been observed once in somatic cancers in COSMIC (COSV55394328) and has been reported in ClinVar as a variant of uncertain significance with one clinical laboratory submission.

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,611,766 alleles (AF 0.00019%), with a highest observed population frequency of 0.00025% in European non-Finnish individuals, which is below the 0.1% PM2 threshold.

Available computational evidence does not support a splice effect, with a SpliceAI maximum delta score of 0.01, and the REVEL score of 0.363 does not provide concordant evidence for either a pathogenic or benign missense effect.

Final determination: The single moderate criterion PM2 does not meet ACMG/AMP combination requirements for likely pathogenic, likely benign, benign, or pathogenic classification; therefore this variant is classified as 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 is a missense variant, NM_002354.3:c.457A>G (p.Arg153Gly), and not a predicted null variant. Available evidence does not support use of a loss-of-function criterion for this change.	prefetch
PS1	Not assessed	No evidence was identified that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant. PS1 cannot be applied from the available data.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. PS2 cannot be assessed from the available evidence.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of p.Arg153Gly were identified. PS3 cannot be applied from the available evidence.
PS4	Not met	This variant has been observed once in COSMIC and is reported in ClinVar as a variant of uncertain significance from a single clinical laboratory, but these data do not demonstrate enrichment in affected individuals over controls. Available evidence does not support PS4.	cosmic clinvar
PM1	Not met	This variant does not lie in a statistically significant hotspot, and no evidence was identified that Arg153 is located in a well-established critical functional domain without benign variation. Available evidence does not support PM1.	hotspots
PM2	Met	Population frequency is very low. This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,611,766 alleles (AF 0.00019%), with highest observed subpopulation frequency 0.00025% in European non-Finnish individuals; this is below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context. PM3 cannot be assessed from the available evidence.
PM4	N/A	This variant is a single amino acid substitution and does not change protein length. PM4 is not applicable.	prefetch
PM5	Not assessed	No evidence was identified for a different pathogenic missense change at codon 153 that would support PM5. PM5 cannot be applied from the available data.	clinvar
PM6	Not assessed	No presumed de novo occurrence was identified for this variant. PM6 cannot be assessed from the available evidence.
PP1	Not assessed	No segregation data were identified for this variant. PP1 cannot be assessed from the available evidence.
PP2	Not assessed	No gene-specific evidence was identified showing that pathogenic EPCAM missense variation is a common disease mechanism and that the gene has a low rate of benign missense variation. PP2 cannot be assessed from the available evidence.
PP3	Not met	Available computational evidence does not provide concordant support for a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the REVEL score is 0.363, which does not support a clear damaging prediction.	spliceai prefetch
PP4	Not assessed	No phenotype information was identified showing a highly specific clinical presentation or family history attributable to EPCAM-related disease in a way that supports this variant. PP4 cannot be assessed from the available evidence.
PP5	Not assessed	ClinVar lists this variant as uncertain significance from a single submitter, which does not provide a sufficiently established pathogenic assertion for PP5. PP5 is not applied.	clinvar
BA1	Not met	Population frequency does not meet a stand-alone benign threshold. The highest observed frequency is 0.00025% in gnomAD v4.1, which is below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency is not greater than expected for a benign variant under the default threshold. The highest observed frequency is 0.00025% in gnomAD v4.1, which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults at a count sufficient for BS2. Although no homozygotes are reported in gnomAD v4.1, these data do not support BS2.	gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating a benign effect of p.Arg153Gly were identified. BS3 cannot be applied from the available evidence.
BS4	Not assessed	No segregation studies were identified showing lack of segregation with disease. BS4 cannot be assessed from the available evidence.
BP1	Not assessed	No gene-specific evidence was identified showing that truncating variants predominate as the established disease mechanism for EPCAM in a way that would support a benign interpretation of this missense change. BP1 cannot be assessed from the available evidence.
BP2	Not assessed	No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. BP2 cannot be assessed from the available evidence.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region. BP3 is not applicable.	prefetch
BP4	Not met	Available computational evidence is insufficient to support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the REVEL score of 0.363 is not low enough to provide concordant benign computational evidence.	spliceai prefetch
BP5	Not assessed	No alternate molecular explanation for the observed disease phenotype was identified that would support BP5. BP5 cannot be assessed from the available evidence.
BP6	Not assessed	No reputable benign classification without available supporting evidence was identified. ClinVar lists this variant as uncertain significance, so BP6 is not applied.	clinvar
BP7	N/A	This is not a synonymous or intronic splice-region variant. BP7 is not applicable.	prefetch

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.