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_001317185.2 5_prime_UTR_premature_start_codon_gain

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, Labcorp Genetics (formerly Invitae), G2P, Illumina
CDH1-related diffuse gastric and lobular breast cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary diffuse gastric adenocarcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
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: Unknown 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317185.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	NM_004360.5	MANE Select	c.113C>T	p.Thr38Met	missense	Exon 2 of 16	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317185.2		c.-1503C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001304114.1
CDH1	NM_001317186.2		c.-1707C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001304115.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	ENST00000261769.10	TSL:1 MANE Select	c.113C>T	p.Thr38Met	missense	Exon 2 of 16	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6	TSL:1	c.113C>T	p.Thr38Met	missense	Exon 2 of 15	ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5	TSL:1	n.113C>T		non_coding_transcript_exon	Exon 2 of 15	ENSP00000454782.1	H3BNC6

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

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (3)

not provided (2)

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

Familial cancer of breast;C1140680:Ovarian cancer (1)

Hereditary diffuse gastric adenocarcinoma (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

0.12

Eigen_PC

Benign

-0.015

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.80

M_CAP

Benign

0.040

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

PhyloP100

0.29

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

REVEL

Benign

0.19

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.025

Polyphen

1.0

Vest4

0.62

MutPred

0.53

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

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