16-68812233-C-A

Position:

• chr16-68812233-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_004360.5(CDH1):​c.1107C>A​(p.Asn369Lys) 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 (★). Synonymous variant affecting the same amino acid position (i.e. N369N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: -0.0420

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 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1107C>A	p.Asn369Lys	missense_variant	8/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1107C>A	p.Asn369Lys	missense_variant	8/15		NP_001304113.1
CDH1	NM_001317185.2	c.-509C>A		5_prime_UTR_variant	8/16		NP_001304114.1
CDH1	NM_001317186.2	c.-713C>A		5_prime_UTR_variant	8/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1107C>A	p.Asn369Lys	missense_variant	8/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Blepharocheilodontic syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2022

- -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2022

- -

Malignant tumor of prostate Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;T;T;.;.
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.7	D;.;.;.;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;.;.;.;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.90
MutPred		0.74		Gain of methylation at N369 (P = 0.0042);Gain of methylation at N369 (P = 0.0042);Gain of methylation at N369 (P = 0.0042);Gain of methylation at N369 (P = 0.0042);Gain of methylation at N369 (P = 0.0042);
MVP		0.91
MPC		0.97
ClinPred		0.99	D
GERP RS		-2.1
Varity_R		0.94
gMVP		0.94

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: chr16-68846136;