rs781513008

chr16-68810329-G-Achr16-68810329-G-Cchr16-68810329-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 2P and 18B. PM1BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004360.5(CDH1):c.820G>A(p.Gly274Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,982 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G274D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 1 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:6

Conservation

PhyloP100: 3.03

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_004360.5

BP4

Computational evidence support a benign effect (MetaRNN=0.10579485).

BP6

Variant 16-68810329-G-A is Benign according to our data. Variant chr16-68810329-G-A is described in ClinVar as [Benign]. Clinvar id is 186326.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000554 (81/1461752) while in subpopulation SAS AF= 0.000927 (80/86254). AF 95% confidence interval is 0.000763. There are 1 homozygotes in gnomad4_exome. There are 56 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.820G>A	p.Gly274Ser	missense_variant	6/16	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.820G>A	p.Gly274Ser	missense_variant	6/15
CDH1	NM_001317185.2 linkuse as main transcript	c.-796G>A		5_prime_UTR_variant	6/16
CDH1	NM_001317186.2 linkuse as main transcript	c.-1000G>A		5_prime_UTR_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.820G>A	p.Gly274Ser	missense_variant	6/16	1	NM_004360.5	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152112

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:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251432

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135876

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 SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2018	The CDH1 c.820G>A; p.Gly274Ser variant (rs781513008), has been reported in association with gastric cancer in single case report. (Garziera 2013 Clin Exp Med). However, this variant is found in the South Asian population with an allele frequency of 0.07% (22/30,782 alleles) in the Genome Aggregation Database and has been reported in ClinVar with conflicting interpretations (Variation ID: 186326). The glycine at codon 274 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Experimental studies have shown that this missense change does not impact CDH1 protein function (Sanches et al, 2015 and Garzier et al, 2013 PLoS One). Given the limited and conflicting information regarding this variant, its clinical significance is uncertain at this time. -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 274 of the CDH1 protein (p.Gly274Ser). This variant is present in population databases (rs781513008, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with sporadic gastric cancer (PMID: 22543498). ClinVar contains an entry for this variant (Variation ID: 186326). 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. Experimental studies have shown that this missense change does not substantially affect CDH1 function (PMID: 22543498, 24204729, 25388006). 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. -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 16, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 27, 2017	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2018

This variant is associated with the following publications: (PMID: 26182300, 24204729, 25388006, 23431106, 22543498, 28873162) -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 09, 2023

The c.820G>A (p.Gly274Ser) variant has been observed in >10 (25) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000760786.3, SCV000216659.5 and SCV000520889.4). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer or lobular breast cancer (BP2_Strong; SCV000520889.4). The c.820G>A variant has an allele frequency of 0.001037 (0.1037%, 5/4822 alleles) in the South Asian subpopulation of the gnomAD v.3.1 cohort (BS1). In summary, the clinical significance of this variant is benign, ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong, BS1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.20

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;T;.;.

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.055

N;.;.;.;N

MutationTaster

Benign

0.68

D;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-4.3

D;.;.;.;D

REVEL

Benign

0.17

Sift

Benign

0.035

D;.;.;.;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.21

MutPred

0.43

Gain of phosphorylation at G274 (P = 0.0546);Gain of phosphorylation at G274 (P = 0.0546);Gain of phosphorylation at G274 (P = 0.0546);Gain of phosphorylation at G274 (P = 0.0546);Gain of phosphorylation at G274 (P = 0.0546);

MVP

0.79

MPC

0.62

ClinPred

0.23

GERP RS

3.3

Varity_R

0.32

gMVP

0.57

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