chr16-68810297-C-T

Variant names:

• chr16-68810297-C-T
• rs1555515456
• NM_004360.5:c.788C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4 BP6

The NM_004360.5(CDH1):​c.788C>T​(p.Thr263Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.556

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.

• PM1: In a domain Cadherin 2 (size 112) in uniprot entity CADH1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_004360.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26761678).
• BP6: Variant 16-68810297-C-T is Benign according to our data. Variant chr16-68810297-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463793.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.788C>T	p.Thr263Ile	missense_variant	Exon 6 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.788C>T	p.Thr263Ile	missense_variant	Exon 6 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-828C>T		5_prime_UTR_variant	Exon 6 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1032C>T		5_prime_UTR_variant	Exon 6 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.788C>T	p.Thr263Ile	missense_variant	Exon 6 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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. ClinVar contains an entry for this variant (Variation ID: 463793). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 263 of the CDH1 protein (p.Thr263Ile). -

CDH1-related diffuse gastric and lobular breast cancer syndrome Uncertain:1

Dec 11, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 13, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;T;T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M;.;.;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D;.;.;.;D
REVEL	Benign	0.10
Sift	Benign	0.41	T;.;.;.;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.058	B;.;.;.;.
Vest4		0.23
MutPred		0.38		Loss of disorder (P = 0.0373);Loss of disorder (P = 0.0373);Loss of disorder (P = 0.0373);Loss of disorder (P = 0.0373);Loss of disorder (P = 0.0373);
MVP		0.81
MPC		0.31
ClinPred		0.65	D
GERP RS		3.2
Varity_R		0.22
gMVP		0.48

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: rs1555515456; hg19: chr16-68844200; COSMIC: COSV55744684; COSMIC: COSV55744684;