chr2-47377020-T-TC

Variant names:

• chr2-47377020-T-TC
• rs606231204
• NM_002354.3:c.499dupC

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_002354.3(EPCAM):​c.499dupC​(p.Gln167ProfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004848899: Immunohistochemistry on cases and controls showed no staining for EPCAM on the intercellular membrane in individuals homozygous for the variant (Salomon 2011 PMID:21315192, Schnell 2013 PMID:23462293, Alfares 2017 PMID:28454995)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q167Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EPCAM NM_002354.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.568
• Publications: 12 publications found

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), Ambry Genetics, G2P, Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004848899: Immunohistochemistry on cases and controls showed no staining for EPCAM on the intercellular membrane in individuals homozygous for the variant (Salomon 2011 PMID: 21315192, Schnell 2013 PMID: 23462293, Alfares 2017 PMID: 28454995).; SCV000617398: Published functional studies demonstrate a damaging effect (Schnell et al., 2013); SCV005345957: Functional studies in vitro demonstrate that this variant leads to absent cell-surface EPCAM protein expression (Schnell et al. 2013, Figure 2. PubMed ID: 23462293).
• PP5: Variant 2-47377020-T-TC is Pathogenic according to our data. Variant chr2-47377020-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 12774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002354.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	NM_002354.3	MANE Select	c.499dupC	p.Gln167ProfsTer21	frameshift	Exon 5 of 9	NP_002345.2	P16422

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.499dupC	p.Gln167ProfsTer21	frameshift	Exon 5 of 9	ENSP00000263735.4	P16422
	EPCAM	ENST00000405271.5	TSL:5	c.583dupC	p.Gln195ProfsTer21	frameshift	Exon 6 of 10	ENSP00000385476.1	B5MCA4
	EPCAM	ENST00000895681.1		c.499dupC	p.Gln167ProfsTer21	frameshift	Exon 5 of 9	ENSP00000565740.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454666 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724276

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105490

Other (OTH) AF: 0.00 AC: 0 AN: 60142

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Congenital diarrhea 5 with tufting enteropathy (5)
1	-	-	EPCAM-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.57
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs606231204; hg19: chr2-47604159;