rs786202785

Positions:

• chr16-68828281-G-A
• chr16-68828281-G-C
• chr16-68828281-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_004360.5(CDH1):​c.2272G>A​(p.Glu758Lys) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E758G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89

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 9 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, 15 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 chr16-68828282-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1205648.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• PP5: Variant 16-68828281-G-A is Pathogenic according to our data. Variant chr16-68828281-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186218.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2272G>A	p.Glu758Lys	missense_variant	14/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2089G>A	p.Glu697Lys	missense_variant	13/15
CDH1	NM_001317185.2	c.724G>A	p.Glu242Lys	missense_variant	14/16
CDH1	NM_001317186.2	c.307G>A	p.Glu103Lys	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2272G>A	p.Glu758Lys	missense_variant	14/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2014

The p.E758K variant (also known as c.2272G>A), located in coding exon 14 of the CDH1 gene, results from a G to A substitution at nucleotide position 2272. The glutamic acid at codon 758 is replaced by lysine, an amino acid with dissimilar properties. This variant is located in the CDH1 juxtamembrane domain responsible for clustering of cadherins in the cell membrane and for cellular adhesive strength via p120-catenin and was detected by our laboratory in a family with clinical history consistent with Hereditary Diffuse Gastric Cancer. Structurally, the position E758 is important for its negative charge and its location in the p120 interaction motif. Mutating this position from a negative charge to a positive charge would act to repel this interaction (Ishiyama N, et al. Cell 2010 Apr; 141(1):117-28). This can be seen with the studies on the adjacent position E757K (Figueiredo J, et al. Eur. J. Hum. Genet. 2013 Mar; 21(3):301-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 45000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by, PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.1	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.73
MutPred		0.72		Gain of methylation at E758 (P = 0.012);.;.;
MVP		0.97
MPC		0.96
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.95
gMVP		0.92

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: rs786202785; hg19: chr16-68862184;