16-68815615-C-T

Variant names:

• chr16-68815615-C-T
• rs1555516124
• NM_004360.5:c.1421C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004360.5(CDH1):​c.1421C>T​(p.Thr474Ile) 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. 15/21 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)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.92

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]

ENSG00000260798 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2791201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1421C>T	p.Thr474Ile	missense_variant	Exon 10 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1238C>T	p.Thr413Ile	missense_variant	Exon 9 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-128C>T		5_prime_UTR_variant	Exon 10 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-399C>T		5_prime_UTR_variant	Exon 10 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1421C>T	p.Thr474Ile	missense_variant	Exon 10 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:2

Mar 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 474 of the CDH1 protein (p.Thr474Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 463715). 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. -

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome Uncertain:2

Nov 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with isoleucine at codon 474 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders 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. -

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T474I variant (also known as c.1421C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1421. The threonine at codon 474 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in an individual with a personal history of breast cancer (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is not well 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. -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	T;T;T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	L;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D;.;.;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.024	D;.;.;.;T
Sift4G	Uncertain	0.046	D;T;T;T;D
Polyphen		0.018	B;.;.;.;.
Vest4		0.34
MutPred		0.53		Loss of glycosylation at T474 (P = 0.0147);Loss of glycosylation at T474 (P = 0.0147);.;Loss of glycosylation at T474 (P = 0.0147);.;
MVP		0.75
MPC		0.30
ClinPred		0.53	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.099
gMVP		0.49

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: rs1555516124; hg19: chr16-68849518;