16-68801670-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_004360.5(CDH1):c.164T>C(p.Val55Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,460,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V55M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense, splice_region

Scores

Splicing: ADA: 0.9257

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.02

Publications

7 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_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 35 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 chr16-68738411-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 819725.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.164T>C	p.Val55Ala	missense_variant, splice_region_variant	Exon 3 of 16	ENST00000261769.10	NP_004351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.164T>C	p.Val55Ala	missense_variant, splice_region_variant	Exon 3 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251390

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460268

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110560

Other (OTH)

AF:

0.00

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 55 of the CDH1 protein (p.Val55Ala). This variant is present in population databases (rs587778174, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 406619). 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. -

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Feb 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with alanine at codon 55 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 breast cancer in the literature (PMID: 25186627, 36436516). This variant has been identified in 1/251390 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. -

Apr 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V55A variant (also known as c.164T>C) is located in coding exon 3 of the CDH1 gene. The valine at codon 55 is replaced by alanine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 3. This variant has been observed in an individuals with a personal and/or family history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;T;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.0

M;.;.;.;M

PhyloP100

6.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.7

D;.;.;.;D

REVEL

Uncertain

0.48

Sift

Benign

0.037

D;.;.;.;D

Sift4G

Benign

0.062

T;D;T;D;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.72

MutPred

0.77

Loss of stability (P = 0.0419);Loss of stability (P = 0.0419);Loss of stability (P = 0.0419);Loss of stability (P = 0.0419);Loss of stability (P = 0.0419);

MVP

0.89

MPC

0.96

ClinPred

0.93

GERP RS

5.4

Varity_R

0.42

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.68

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