NM_004360.5:c.1679C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_004360.5(CDH1):c.1679C>T(p.Thr560Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T560R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 1.21

Publications

20 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:

ENSG00000260798 (HGNC:):

ENSG00000260798 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 40 uncertain in NM_004360.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-68819393-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 234554.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH1	NM_004360.5 link	c.1679C>T	p.Thr560Met	missense_variant	Exon 11 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.1496C>T	p.Thr499Met	missense_variant	Exon 10 of 15		NP_001304113.1
CDH1	NM_001317185.2 link	c.131C>T	p.Thr44Met	missense_variant	Exon 11 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.-254-2608C>T		intron_variant	Intron 10 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.1679C>T	p.Thr560Met	missense_variant	Exon 11 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251482

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727064

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000267

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:4

Oct 26, 2022

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 560 of the CDH1 protein (p.Thr560Met). This variant is present in population databases (rs746481984, gnomAD 0.004%). 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: 188085). 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 (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Mar 20, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 03, 2023

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 18, 2019

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.1679C>T (p.Thr560Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance (Momozawa_2018 and gnomAD). To our knowledge, no occurrence of c.1679C>T in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:2

Nov 23, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_moderate -

Aug 22, 2023

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 does not alter protein structure/function; Identified in unaffected individual(s) but not in any cases from a breast cancer study (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 36243179, 15235021, 22850631, 30287823) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T560M variant (also known as c.1679C>T), located in coding exon 11 of the CDH1 gene, results from a C to T substitution at nucleotide position 1679. The threonine at codon 560 is replaced by methionine, an amino acid with similar properties. In one study, this variant was detected with a carrier frequency of 0.0001 in 12490 male controls of Japanese ancestry and was not detected in 7051 unselected breast cancer patients, 53 male breast cancer patients or 11241 female controls in the same study (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration has also been identified in an East Asian patient with a sarcoma diagnosed at age 35 (Ballinger ML et al. Lancet Oncol, 2016 Sep;17:1261-71), and was reported in 1/701 Brazilian individuals with features consistent with a hereditary breast and/or ovarian cancer syndrome (Faria JP et al. Breast Cancer Res Treat, 2024 Jun). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

May 22, 2023

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 560 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sarcoma (PMID: 27498913) and in an individual unaffected with cancer (PMID: 30287823). This variant has been identified in 1/251482 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. -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Uncertain:1

Oct 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:1

Sep 20, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.90

D;T;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.52

D;D;D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.3

M;.;.;.;.

PhyloP100

1.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

N;.;.;.;N

REVEL

Benign

0.26

Sift

Benign

0.15

T;.;.;.;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.63

MutPred

0.55

Loss of glycosylation at S559 (P = 0.0254);Loss of glycosylation at S559 (P = 0.0254);.;Loss of glycosylation at S559 (P = 0.0254);.;

MVP

0.86

MPC

0.91

ClinPred

0.94

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.48

Mutation Taster

=42/58

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over