rs1555516147

chr16-68815662-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004360.5(CDH1):c.1468G>A(p.Glu490Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. E490G) 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: 0.797

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12768018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1468G>A	p.Glu490Lys	missense_variant	10/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1285G>A	p.Glu429Lys	missense_variant	9/15
CDH1	NM_001317185.2	c.-81G>A		5_prime_UTR_variant	10/16
CDH1	NM_001317186.2	c.-352G>A		5_prime_UTR_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1468G>A	p.Glu490Lys	missense_variant	10/16	1	NM_004360.5	P1
	ENST00000563916.1	n.264-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2020	In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This sequence change replaces glutamic acid with lysine at codon 490 of the CDH1 protein (p.Glu490Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CDH1-related disease. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2022

The p.E490K variant (also known as c.1468G>A), located in coding exon 10 of the CDH1 gene, results from a G to A substitution at nucleotide position 1468. The glutamic acid at codon 490 is replaced by lysine, an amino acid with similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This amino acid position is poorly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Benign	0.61
DEOGEN2	Uncertain	0.43	T;T;T;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.2	N;.;.;.;N
REVEL	Benign	0.040
Sift	Benign	0.57	T;.;.;.;T
Sift4G	Benign	0.55	T;T;T;T;T
Polyphen		0.039	B;.;.;.;.
Vest4		0.20
MutPred		0.41		Gain of methylation at E490 (P = 0.0261);Gain of methylation at E490 (P = 0.0261);.;Gain of methylation at E490 (P = 0.0261);.;
MVP		0.74
MPC		0.30
ClinPred		0.057	T
GERP RS		2.7
Varity_R		0.031
gMVP		0.29

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: rs1555516147; hg19: chr16-68849565; COSMIC: COSV55738490; COSMIC: COSV55738490;