2-47373855-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_002354.3(EPCAM):c.232C>G(p.Leu78Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L78P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 1 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.292

Publications

5 publications found

Variant links:

Genes affected

EPCAM (HGNC:11529): (epithelial cell adhesion molecule) This gene encodes a carcinoma-associated antigen and is a member of a family that includes at least two type I membrane proteins. This antigen is expressed on most normal epithelial cells and gastrointestinal carcinomas and functions as a homotypic calcium-independent cell adhesion molecule. The antigen is being used as a target for immunotherapy treatment of human carcinomas. Mutations in this gene result in congenital tufting enteropathy. [provided by RefSeq, Dec 2008]

EPCAM Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital diarrhea 5 with tufting enteropathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EPCAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015308827).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000067 (98/1461866) while in subpopulation EAS AF = 0.000504 (20/39700). AF 95% confidence interval is 0.000333. There are 1 homozygotes in GnomAdExome4. There are 37 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.232C>G	p.Leu78Val	missense_variant	Exon 3 of 9	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9 link	c.232C>G	p.Leu78Val	missense_variant	Exon 3 of 9	1	NM_002354.3	ENSP00000263735.4

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251450

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000670

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111988

Other (OTH)

AF:

0.000745

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41370

American (AMR)

AF:

0.0000657

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000771

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 8;C2750737:Congenital diarrhea 5 with tufting enteropathy

Uncertain:2

Feb 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Lynch syndrome 8

Uncertain:1

Feb 02, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The EPCAM c.232C>G (p.Leu78Val) missense variant has a maximum subpopulation frequency of 0.055% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was reported in at least one individual with familial colorectal cancer (PMID: 29212164) and in an individual with peritoneum cancer and a family history of cancer (PMID: 30093976). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided

Uncertain:1

Dec 19, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with EPCAM-related disease. ClinVar contains an entry for this variant (Variation ID: 136018). This variant is present in population databases (rs587780763, ExAC 0.06%). This sequence change replaces leucine with valine at codon 78 of the EPCAM protein (p.Leu78Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. -

EPCAM-related disorder

Uncertain:1

Jun 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EPCAM c.232C>G variant is predicted to result in the amino acid substitution p.Leu78Val. This variant was reported as a variant of uncertain significance in an individual with peritoneal cancer and a family history of cancer (Supp. Table 2 in Chan et al. 2018. PubMed ID: 30093976). This variant was also reported in a cohort study of individuals with colorectal cancer (Supp. Table 1 Raskin. 2017. PubMed ID: 29212164) and in a patient with breast cancer and family history of ovarian cancer (Supp. Table 4 in Bhai P et al 2021. PubMed ID: 34326862). This variant is reported in 0.055% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/136018/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.2

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.012

T;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.57

.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;N;.

PhyloP100

-0.29

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.38

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.032

B;B;.

Vest4

0.11

MutPred

0.27

Gain of MoRF binding (P = 0.0878);.;.;

MVP

0.17

MPC

0.014

ClinPred

0.10

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.078

gMVP

0.33

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over