16-68801859-C-G

Position:

• chr16-68801859-C-G

Variant summary

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

The NM_004360.5(CDH1):​c.353C>G​(p.Thr118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.672

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.353C>G	p.Thr118Arg	missense_variant	3/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.353C>G	p.Thr118Arg	missense_variant	3/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1263C>G		5_prime_UTR_variant	3/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1467C>G		5_prime_UTR_variant	3/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.353C>G	p.Thr118Arg	missense_variant	3/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 118 of the CDH1 protein (p.Thr118Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 17221870). ClinVar contains an entry for this variant (Variation ID: 142730). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 17221870, 19268661). 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The p.T118R variant (also known as c.353C>G), located in coding exon 3 of the CDH1 gene, results from a C to G substitution at nucleotide position 353. The threonine at codon 118 is replaced by arginine, an amino acid with similar properties. This alteration has been identified in an individual with personal history of diffuse gastric cancer and family history of gastric cancer, type unspecified (Suriano G, et al. J. Mol. Med. 2006 Dec; 84(12):1023-31). Functional studies have shown that p.T118R mutants display an increase in cell migration and invasion potential due to reduced cell to cell adhesion, a known function of E-cadherin (Suriano G, et al. J. Mol. Med. 2006 Dec; 84(12):1023-31. More H, et al. Hum. Mutat. 2007 Feb; 28(2):203). Another study has demonstrated decreased stability of the EGFR/E-cadherin heteromers, resulting in increased EGRF activity (Mateus AR, et al. Exp. Cell Res. 2009 May; 315(8):1393-402). 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	0.092
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	1.3
DANN	Benign	0.69
DEOGEN2	Benign	0.25	T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.46	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.53	N;.;.;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.63	T;.;.;.;T
Sift4G	Benign	0.68	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.32
MutPred		0.84		Loss of glycosylation at T118 (P = 0.0131);Loss of glycosylation at T118 (P = 0.0131);Loss of glycosylation at T118 (P = 0.0131);Loss of glycosylation at T118 (P = 0.0131);Loss of glycosylation at T118 (P = 0.0131);
MVP		0.62
MPC		0.29
ClinPred		0.013	T
GERP RS		-1.4
Varity_R		0.057
gMVP		0.30

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: rs587782677; hg19: chr16-68835762;