16-68813347-T-G

Variant names:

• chr16-68813347-T-G
• rs1555515873
• NM_004360.5:c.1172T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004360.5(CDH1):​c.1172T>G​(p.Val391Gly) 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:2
• Conservation: PhyloP100: -0.171

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17371073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1172T>G	p.Val391Gly	missense_variant	Exon 9 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317185.2	c.-444T>G		5_prime_UTR_variant	Exon 9 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-648T>G		5_prime_UTR_variant	Exon 9 of 15		NP_001304115.1
CDH1	NM_001317184.2	c.1137+1084T>G		intron_variant	Intron 8 of 14		NP_001304113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1172T>G	p.Val391Gly	missense_variant	Exon 9 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Jun 02, 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 483236). 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 valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 391 of the CDH1 protein (p.Val391Gly). -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 30, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V391G variant (also known as c.1172T>G), located in coding exon 9 of the CDH1 gene, results from a T to G substitution at nucleotide position 1172. The valine at codon 391 is replaced by glycine, 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. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 240000 alleles tested) in our clinical cohort. This amino acid position is poorly 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	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.3
DANN	Benign	0.88
DEOGEN2	Uncertain	0.46	T;T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.1	D;.;.;.
REVEL	Benign	0.057
Sift	Benign	0.12	T;.;.;.
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.058	B;.;.;.
Vest4		0.35
MutPred		0.58		Loss of stability (P = 0.014);Loss of stability (P = 0.014);Loss of stability (P = 0.014);Loss of stability (P = 0.014);
MVP		0.55
MPC		0.38
ClinPred		0.084	T
GERP RS		-1.7
Varity_R		0.18
gMVP		0.56

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: rs1555515873; hg19: chr16-68847250;