16-68738309-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.61C>G (p.Leu21Val) variant results in a non-synonymous amino acid change in exon 2. This variant is present in 5 of 188,446 alleles (0.00003) in gnomAD, present exclusively in the East Asian subpopulation with 5 of 12,882 alleles (0.00039). This variant has been observed in at least three individuals without DGC, SRC tumour or LBC and whose families do not suggest HDGC (BS2_supporting). In summary, the clinical significance of this variant is uncertain based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580066/MONDO:0007648/007

Frequency

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

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:5B:1

Conservation

PhyloP100: 0.584

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: Uncertain_significance. The variant received -1 ACMG points.

BS2

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH1	NM_004360.5	MANE Select	c.61C>G	p.Leu21Val	missense	Exon 2 of 16	NP_004351.1
CDH1	NM_001317184.2		c.61C>G	p.Leu21Val	missense	Exon 2 of 15	NP_001304113.1
CDH1	NM_001317185.2		c.-1555C>G		5_prime_UTR	Exon 2 of 16	NP_001304114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH1	ENST00000261769.10	TSL:1 MANE Select	c.61C>G	p.Leu21Val	missense	Exon 2 of 16	ENSP00000261769.4
CDH1	ENST00000422392.6	TSL:1	c.61C>G	p.Leu21Val	missense	Exon 2 of 15	ENSP00000414946.2
CDH1	ENST00000566612.5	TSL:1	n.61C>G		non_coding_transcript_exon	Exon 2 of 15	ENSP00000454782.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

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

GnomAD2 exomes

AF:

0.0000255

AC:

AN:

157096

AF XY:

0.0000241

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000353

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000501

AC:

AN:

1398254

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31564

American (AMR)

AF:

0.00

AC:

AN:

35690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.0000559

AC:

AN:

35810

South Asian (SAS)

AF:

0.00

AC:

AN:

79200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000464

AC:

AN:

1077992

Other (OTH)

AF:

0.00

AC:

AN:

57954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

Hereditary diffuse gastric adenocarcinoma (2)

CDH1-related diffuse gastric and lobular breast cancer syndrome (1)

Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.8

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.32

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.56

M_CAP

Benign

0.012

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.70

PhyloP100

0.58

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.70

REVEL

Benign

0.024

Sift

Benign

0.52

Sift4G

Benign

0.64

Polyphen

0.0

Vest4

0.47

MutPred

0.37

Gain of loop (P = 0.0097)

MVP

0.53

MPC

0.25

ClinPred

0.015

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.039

gMVP

0.19

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over