16-68801691-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_004360.5(CDH1):c.185G>T(p.Gly62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G62S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.13

Publications

14 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 31 uncertain in NM_004360.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH1	NM_004360.5 link	c.185G>T	p.Gly62Val	missense_variant	Exon 3 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.185G>T	p.Gly62Val	missense_variant	Exon 3 of 15		NP_001304113.1
CDH1	NM_001317185.2 link	c.-1431G>T		5_prime_UTR_variant	Exon 3 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.-1635G>T		5_prime_UTR_variant	Exon 3 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.185G>T	p.Gly62Val	missense_variant	Exon 3 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000630

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111894

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Aug 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G62V variant (also known as c.185G>T), located in coding exon 3 of the CDH1 gene, results from a G to T substitution at nucleotide position 185. The glycine at codon 62 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in one Japanese male who was diagnosed with diffuse gastric cancer at age 61; he reported having three brothers diagnosed with gastric cancer and both parents diagnosed with gastric cancer (Shinmura K et al, Carcinogenesis 1999 Jun; 20(6):1127-31). This alteration has also been reported in a Brazilian family, wherein both a father and son were diagnosed with diffuse gastric cancer at ages 36 and 31; another daughter was diagnosed with diffuse gastric cancer at 37 and was not tested. Further, testing of tumor cells for the father revealed negative immunoreactivity to the E-cadherin protein (Moreira-Nunes CA et al, Hered Cancer Clin Pract 2014 ; 12(1):18). This alteration was observed in 14/7051 unselected female breast cancer patients; however it was also observed in 48/11241 female controls and 43/12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

May 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with valine at codon 62 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with diffuse gastric cancer and breast cancer (PMID: 10357799, 25180051, 30287823, 32426482), but also in unaffected individuals (PMID: 30287823, 32426482). This variant has not been identified 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.

not specified

Uncertain:1

Jul 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDH1 c.185G>T (p.Gly62Val) results in a non-conservative amino acid change located in the Cadherin prodomain (IPR014868) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0005 in 376334 control chromosomes (exclusively in Japanese population, allele frequency 0.0015, Momozawa_2018 jMorp database). The observed variant frequency is approximately 17-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05). c.185G>T has been observed in individual(s) affected with Hereditary Diffuse Gastric Cancer (Moreira-Nunes_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19725995, 30287823, 25180051, 36243179, 10357799, 22470475). ClinVar contains an entry for this variant (Variation ID: 187429). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Familial cancer of breast;C1140680:Ovarian cancer

Uncertain:1

Jun 13, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jul 17, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20373070, 16527687, 16787116, 22470475, 21777349, 15457549, 16501831, 12647996, 20233471, 10357799, 25180051, 22225527, 15235021, 32426482, 33809393, 30287823, 35685475)

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 62 of the CDH1 protein (p.Gly62Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with diffuse gastric cancer and/or intestinal gastric cancer (PMID: 10357799, 25180051, 30745422, 32426482). ClinVar contains an entry for this variant (Variation ID: 187429). 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 disruptive. 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;T;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.7

M;.;.;.;M

PhyloP100

2.1

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.0

D;.;.;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0060

D;.;.;.;D

Sift4G

Uncertain

0.050

T;D;T;D;T

Vest4

0.52

ClinPred

0.99

GERP RS

5.4

Varity_R

0.72

gMVP

0.61

Mutation Taster

=28/72

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over