chr16-68822072-C-T

Position:

chr16-68822072-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_004360.5(CDH1):c.1783C>T(p.Pro595Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P595R) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.58

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3991961).

BS2

High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.1783C>T	p.Pro595Ser	missense_variant	12/16	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.1600C>T	p.Pro534Ser	missense_variant	11/15
CDH1	NM_001317185.2 linkuse as main transcript	c.235C>T	p.Pro79Ser	missense_variant	12/16
CDH1	NM_001317186.2 linkuse as main transcript	c.-183C>T		5_prime_UTR_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.1783C>T	p.Pro595Ser	missense_variant	12/16	1	NM_004360.5	P1	P12830-1
	ENST00000563916.1 linkuse as main transcript	n.263+1192G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251490

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000616

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 04, 2020	This missense variant replaces proline with serine at codon 595 of the CDH1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282892 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 26, 2023	The p.P595S variant (also known as c.1783C>T), located in coding exon 12 of the CDH1 gene, results from a C to T substitution at nucleotide position 1783. The proline at codon 595 is replaced by serine, an amino acid with similar properties. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 595 of the CDH1 protein (p.Pro595Ser). This variant is present in population databases (rs755622441, gnomAD 0.006%). 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: 463730). 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

Pathogenic

0.74

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;T;T;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.40

T;T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.0

M;.;.;.;.

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.2

D;.;.;.;D

REVEL

Uncertain

0.33

Sift

Benign

0.041

D;.;.;.;D

Sift4G

Uncertain

0.057

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.50

MutPred

0.46

Gain of phosphorylation at P595 (P = 0.0833);Gain of phosphorylation at P595 (P = 0.0833);.;Gain of phosphorylation at P595 (P = 0.0833);.;

MVP

0.90

MPC

0.67

ClinPred

0.96

GERP RS

5.3

Varity_R

0.54

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over