rs1017050648

Positions:

• chr16-68811744-C-A
• chr16-68811744-C-G
• chr16-68811744-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_004360.5(CDH1):​c.893C>A​(p.Ala298Asp) 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 pathogenic 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. A298T) has been classified as Benign.

• 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: 3.21

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 Likely_pathogenic. Variant got 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-68811743-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.893C>A	p.Ala298Asp	missense_variant	7/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.893C>A	p.Ala298Asp	missense_variant	7/15		NP_001304113.1
CDH1	NM_001317185.2	c.-723C>A		5_prime_UTR_variant	7/16		NP_001304114.1
CDH1	NM_001317186.2	c.-927C>A		5_prime_UTR_variant	7/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.893C>A	p.Ala298Asp	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

Oct 06, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CDH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with aspartic acid at codon 298 of the CDH1 protein (p.Ala298Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2021

The p.A298D variant (also known as c.893C>A), located in coding exon 7 of the CDH1 gene, results from a C to A substitution at nucleotide position 893. The alanine at codon 298 is replaced by aspartic acid, an amino acid with dissimilar 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	N;.;.;.;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;.;.;.;D
Sift4G	Uncertain	0.0040	D;T;D;T;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.68
MutPred		0.80		Loss of glycosylation at T295 (P = 0.0822);Loss of glycosylation at T295 (P = 0.0822);Loss of glycosylation at T295 (P = 0.0822);Loss of glycosylation at T295 (P = 0.0822);Loss of glycosylation at T295 (P = 0.0822);
MVP		0.88
MPC		1.1
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.85

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: rs1017050648; hg19: chr16-68845647; COSMIC: COSV55745737; COSMIC: COSV55745737;