rs1555518257

chr16-68833410-G-Achr16-68833410-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004360.5(CDH1):c.2560G>A(p.Asp854Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. D854A) has been classified 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: 4.44

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29062968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2560G>A	p.Asp854Asn	missense_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2377G>A	p.Asp793Asn	missense_variant	15/15
CDH1	NM_001317185.2	c.1012G>A	p.Asp338Asn	missense_variant	16/16
CDH1	NM_001317186.2	c.595G>A	p.Asp199Asn	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2560G>A	p.Asp854Asn	missense_variant	16/16	1	NM_004360.5	P1

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

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Uncertain	0.0022	D
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.28	T;.;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.16
MutPred		0.63		Gain of methylation at K855 (P = 0.1424);.;.;
MVP		0.94
MPC		0.71
ClinPred		0.92	D
GERP RS		6.2
Varity_R		0.25
gMVP		0.68

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: rs1555518257; hg19: chr16-68867313;