16-68738361-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS2PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.113C>T (p.Thr38Met) variant results in a non-synonymous amino acid substitution in exon 2 of CDH1. The variant allele occurs in 1 of 156,704 alleles in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in 1 of 1,362 alleles among individuals undergoing genome sequencing who are not known to meet IGCLC criteria for HDGC (PMID:24728327). In addition, this variant has been observed in at least 10 individuals without DGC, LBC or SRC tumors and whose families do not suggest HDGC (BS2; SCV000666274.3, SCV000567622.4, SCV000954584.2). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157971/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:2O:1

Conservation

PhyloP100: 0.288

Publications

3 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: Likely_benign. The variant received -3 ACMG points.

PM2

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

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.113C>T	p.Thr38Met	missense_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH1	ENST00000261769.10 link	c.113C>T	p.Thr38Met	missense_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6 link	c.113C>T	p.Thr38Met	missense_variant	Exon 2 of 15	1		ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5 link	n.113C>T		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1	H3BNC6
CDH1	ENST00000566510.5 link	n.113C>T		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1	H3BVI7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000638

AC:

AN:

156704

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000890

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000429

AC:

AN:

1398866

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

689938

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31586

American (AMR)

AF:

0.00

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35768

South Asian (SAS)

AF:

0.00

AC:

AN:

79184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078750

Other (OTH)

AF:

0.00

AC:

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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:

0.0000282

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Jun 28, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces threonine with methionine at codon 38 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a healthy individual (PMID: 24728327) and has not been reported in an individual affected with CDH1-related disorders. This variant has been identified in 1/156704 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 04, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nov 23, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Uncertain:2

Jan 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDH1 c.113C>T (p.Thr38Met) variant has been reported in the published literature in in reportedly healthy individuals (PMID: 24728327 (2014)). The frequency of this variant in the general population, 0.0000064 (1/156704 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 27, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted CDH1 c.113C>T at the cDNA level, p.Thr38Met (T38M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). CDH1 Thr38Met was identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. CDH1 Thr38Met was not observed in approximately 5,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Thr38Met occurs at a position that is not conserved and is not located in a known functional domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CDH1 Thr38Met is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Familial cancer of breast;C1140680:Ovarian cancer

Uncertain:1

Feb 09, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 38 of the CDH1 protein (p.Thr38Met). This variant is present in population databases (rs587778171, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 133850). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Aug 18, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.113C>T (p.Thr38Met) variant results in a non-synonymous amino acid substitution in exon 2 of CDH1. The variant allele occurs in 1 of 156,704 alleles in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in 1 of 1,362 alleles among individuals undergoing genome sequencing who are not known to meet IGCLC criteria for HDGC (PMID: 24728327). In addition, this variant has been observed in at least 10 individuals without DGC, LBC or SRC tumors and whose families do not suggest HDGC (BS2; SCV000666274.3, SCV000567622.4, SCV000954584.2). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, PM2_supporting. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T;T;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

-0.015

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.80

T;T;T;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

L;.;.;.;L

PhyloP100

0.29

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;.;.;.;N

REVEL

Benign

0.19

Sift

Uncertain

0.0030

D;.;.;.;D

Sift4G

Uncertain

0.025

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.62

MutPred

0.53

Loss of phosphorylation at T40 (P = 0.0749);Loss of phosphorylation at T40 (P = 0.0749);Loss of phosphorylation at T40 (P = 0.0749);Loss of phosphorylation at T40 (P = 0.0749);Loss of phosphorylation at T40 (P = 0.0749);

MVP

0.85

MPC

0.32

ClinPred

0.28

GERP RS

1.6

Varity_R

0.20

gMVP

0.33

Mutation Taster

=88/12

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

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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