16-68810240-A-T

Position:

• chr16-68810240-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_004360.5(CDH1):​c.731A>T​(p.Asp244Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D244G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

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 6 ACMG points.

• PM1: In a domain Cadherin 1 (size 107) in uniprot entity CADH1_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) 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 chr16-68810240-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.731A>T	p.Asp244Val	missense_variant	6/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.731A>T	p.Asp244Val	missense_variant	6/15		NP_001304113.1
CDH1	NM_001317185.2	c.-885A>T		5_prime_UTR_variant	6/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1089A>T		5_prime_UTR_variant	6/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.731A>T	p.Asp244Val	missense_variant	6/16	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The p.D244V variant (also known as c.731A>T), located in coding exon 6 of the CDH1 gene, results from an A to T substitution at nucleotide position 731. The aspartic acid at codon 244 is replaced by valine, an amino acid with highly 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	Benign	0.32
BayesDel_addAF	Benign	0.0096	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;T;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D;T;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.1	M;.;.;.;M
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.5	D;.;.;.;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D;.;.;.;D
Sift4G	Uncertain	0.048	D;D;D;D;D
Polyphen		0.98	D;.;.;.;.
Vest4		0.59
MutPred		0.60		Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);
MVP		0.90
MPC		1.0
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68844143;