16-68822132-A-T

Variant names:

• chr16-68822132-A-T
• rs1003012321
• NM_004360.5:c.1843A>T

Variant summary

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

The NM_004360.5(CDH1):​c.1843A>T​(p.Ile615Phe) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I615T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.454

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=0.26835224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1843A>T	p.Ile615Phe	missense_variant	Exon 12 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1660A>T	p.Ile554Phe	missense_variant	Exon 11 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.295A>T	p.Ile99Phe	missense_variant	Exon 12 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-123A>T		5_prime_UTR_variant	Exon 11 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1843A>T	p.Ile615Phe	missense_variant	Exon 12 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Oct 19, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with phenylalanine at codon 615 of the CDH1 protein (p.Ile615Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

Jun 26, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I615F variant (also known as c.1843A>T), located in coding exon 12 of the CDH1 gene, results from an A to T substitution at nucleotide position 1843. The isoleucine at codon 615 is replaced by phenylalanine, an amino acid with highly similar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.0
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;.;.;N
REVEL	Benign	0.057
Sift	Benign	0.069	T;.;.;T
Sift4G	Benign	0.068	T;T;T;T
Polyphen		0.75	P;.;.;.
Vest4		0.091
MutPred		0.49		Loss of stability (P = 0.0483);.;Loss of stability (P = 0.0483);.;
MVP		0.79
MPC		0.41
ClinPred		0.22	T
GERP RS		-1.0
Varity_R		0.11
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1003012321; hg19: chr16-68856035;