16-68808811-C-T

Position:

• chr16-68808811-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004360.5(CDH1):​c.650C>T​(p.Thr217Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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:3
• Conservation: PhyloP100: 2.29

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]

CDH1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Cadherin 1 (size 107) in uniprot entity CADH1_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_004360.5
• 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.650C>T	p.Thr217Ile	missense_variant	5/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.650C>T	p.Thr217Ile	missense_variant	5/15		NP_001304113.1
CDH1	NM_001317185.2	c.-966C>T		5_prime_UTR_variant	5/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1170C>T		5_prime_UTR_variant	5/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.650C>T	p.Thr217Ile	missense_variant	5/16	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: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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2020

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. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231975). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 217 of the CDH1 protein (p.Thr217Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 20, 2024

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2022

The p.T217I variant (also known as c.650C>T), located in coding exon 5 of the CDH1 gene, results from a C to T substitution at nucleotide position 650. The threonine at codon 217 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.74
DEOGEN2	Uncertain	0.54	D;T;T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.1	D;.;.;.;D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.58
MutPred		0.67		Gain of catalytic residue at P219 (P = 0.0282);Gain of catalytic residue at P219 (P = 0.0282);Gain of catalytic residue at P219 (P = 0.0282);Gain of catalytic residue at P219 (P = 0.0282);Gain of catalytic residue at P219 (P = 0.0282);
MVP		0.88
MPC		0.94
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.65

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: rs778382252; hg19: chr16-68842714;