rs1064794232

Positions:

• chr16-68828278-G-A
• chr16-68828278-G-C
• chr16-68828278-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004360.5(CDH1):​c.2269G>A​(p.Glu757Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. E757G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_004360.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2269G>A	p.Glu757Lys	missense_variant	14/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2086G>A	p.Glu696Lys	missense_variant	13/15
CDH1	NM_001317185.2	c.721G>A	p.Glu241Lys	missense_variant	14/16
CDH1	NM_001317186.2	c.304G>A	p.Glu102Lys	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2269G>A	p.Glu757Lys	missense_variant	14/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2023

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. Experimental studies have shown that this missense change affects CDH1 function (PMID: 18772194, 19268661, 22850631, 25388006). 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. ClinVar contains an entry for this variant (Variation ID: 420006). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 18772194). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 757 of the CDH1 protein (p.Glu757Lys). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2021

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate lower e-cadherin expression, increased invasion, decreased aggregation, and reduction of p120-catenin interaction (Simoes-Correia 2008, Mateus 2009, Sanches 2015, Figueiredo 2013); Observed in individuals with diffuse gastric cancer (Simoes-Correia 2008, Oliveira 2009, Pinheiro 2010); This variant is associated with the following publications: (PMID: 18772194, 21853084, 19268661, 25388006, 22850631, 22613680, 22225527, 19965908, 19269290, 20373070, 15235021, 30311375) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 16, 2022

This missense variant replaces glutamic acid with lysine at codon 757 of the CDH1 protein. Experimental functional studies in cell lines have reported this variant to have partial effect on CDH1 function, including reduced surface and total CDH1 protein expression, beta-catenin interaction, and cell-cell adhesion, and increased retention in the endoplasmic reticulum, cell invasion and cell motiility (PMID: 18772194, 19268661, 21853084, 22613680, 22850631, 25388006). This variant has been reported in individuals from one family affected with diffuse gastric cancer in the literature. This variant has not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;T;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.6	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.75
MutPred		0.84		Gain of sheet (P = 0.0043);.;.;
MVP		0.97
MPC		0.96
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.86

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

Other links and lift over

dbSNP: rs1064794232; hg19: chr16-68862181;