16-68737417-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2_SupportingPS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.2T>G (p.Met1Arg) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in two probands/families meeting HDGC clinical criteria (PS4_Moderate; SCV000760846.2 and internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 2 as specified by the CDH1 Variant Curation Expert Panel (v3.1): PVS1, PM2_supporting, PS4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396451182/MONDO:0007648/007

Frequency

Genomes: not found (cov: 33)

Consequence

CDH1
NM_004360.5 start_lost

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 1.35

Publications

1 publications found

Variant links:

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

CDH1 Gene-Disease associations (from GenCC):

blepharocheilodontic syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
CDH1-related diffuse gastric and lobular breast cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary diffuse gastric adenocarcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
cleft soft palate
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
orofacial cleft 3
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
blepharocheilodontic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CDH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH1	NM_004360.5 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 15		NP_001304113.1
CDH1	NM_001317185.2 link	c.-1614T>G		5_prime_UTR_variant	Exon 1 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.-1818T>G		5_prime_UTR_variant	Exon 1 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDH1	ENST00000261769.10 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5 link	n.2T>G		non_coding_transcript_exon_variant	Exon 1 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5 link	n.2T>G		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Pathogenic:2

Nov 27, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the CDH1 mRNA. The next in-frame methionine is located at codon 246. For these reasons, this variant has been classified as Pathogenic. Functional studies for this variant have not been reported. However, translation rescue by the downstream methionine at codon 246 would delete most of the first extracellular cadherin (EC1) domain (amino acid residues 155-262). This domain is important for the formation of intermolecular interactions with other CDH1 molecules to establish cell-cell junctions (PMID: 18726070, 2317870, 20066110). Several variants affecting the¬†initiator methionine of the CDH1 mRNA (c.1A>G, c.2T>C, c.3G>C,¬†c.3G>A) have been observed in individuals with a personal or family history of diffuse¬†gastric cancer and/or lobular breast cancer (PMID: 28202063, 16061854,¬†20373070, Invitae). This suggests that variants that disrupt the initiator codon of the CDH1 protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with CDH1-related disease.¬†ClinVar contains an entry for this variant (Variation ID:¬†532474). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database.

Jun 08, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation.

CDH1-related diffuse gastric and lobular breast cancer syndrome

Pathogenic:1

Aug 25, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.2T>G (p.Met1Arg) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in two probands/families meeting HDGC clinical criteria (PS4_Moderate; SCV000760846.2 and internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 2 as specified by the CDH1 Variant Curation Expert Panel (v3.1): PVS1, PM2_supporting, PS4_Moderate.

Hereditary cancer-predisposing syndrome

Pathogenic:1

Feb 18, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant results in the loss of the translation start codon (methionine at codon 1) of the CDH1 gene. This variant is expected to disrupt the expression of the full-length CDH1 protein. Variants at the initiator codon (c.1A>G, c.2T>C, c.3G>C, c.3G>A) that result in the loss of p.Met1 have been observed in families affected with diffuse gastric cancer (PMID: 16061854, 20373070, 26182300) and lobular breast cancer (PMID: 28202063). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

T;T;T;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

.;.;.;.;.

PhyloP100

1.3

PROVEAN

Benign

-0.84

N;.;.;.;N

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.77

ClinPred

0.99

GERP RS

5.0

PromoterAI

-0.27

Neutral

(source)

Varity_R

0.97

gMVP

0.80

Mutation Taster

=3/197

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over