chr16-68811831-G-T

Position:

• chr16-68811831-G-T

Variant summary

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

The NM_001317185.2(CDH1):​c.-636G>T variant causes a 5 prime UTR premature start codon gain 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_001317185.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.10

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 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.980G>T	p.Ser327Ile	missense_variant	7/16	ENST00000261769.10	NP_004351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.980G>T	p.Ser327Ile	missense_variant	7/16	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: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

Dec 15, 2023

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 327 of the CDH1 protein (p.Ser327Ile). 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: 141477). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Jan 29, 2015

The p.S327I variant (also known as c.980G>T), located in coding exon 7 of the CDH1 gene, results from a G to T substitution at nucleotide position 980. The serine at codon 327 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 73000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging but tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.S327I remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.94	L;.;.;.;L
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;.;.;.;D
REVEL	Benign	0.22
Sift	Benign	0.51	T;.;.;.;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.53
MutPred		0.61		Loss of catalytic residue at S327 (P = 0.0548);Loss of catalytic residue at S327 (P = 0.0548);Loss of catalytic residue at S327 (P = 0.0548);Loss of catalytic residue at S327 (P = 0.0548);Loss of catalytic residue at S327 (P = 0.0548);
MVP		0.85
MPC		0.98
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.68
gMVP		0.61

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: rs587781778; hg19: chr16-68845734;