rs878854686

Variant names:

• chr16-68833317-A-C
• NM_004360.5:c.2467A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-68833317-A-C
• chr16-68833317-A-G
• chr16-68833317-A-T

Variant summary

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

The NM_004360.5(CDH1):​c.2467A>C​(p.Thr823Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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, single submitter U:1
• Conservation: PhyloP100: 6.11

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2467A>C	p.Thr823Pro	missense_variant	Exon 16 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2284A>C	p.Thr762Pro	missense_variant	Exon 15 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.919A>C	p.Thr307Pro	missense_variant	Exon 16 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.502A>C	p.Thr168Pro	missense_variant	Exon 15 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2467A>C	p.Thr823Pro	missense_variant	Exon 16 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T823P variant (also known as c.2467A>C), located in coding exon 16 of the CDH1 gene, results from an A to C substitution at nucleotide position 2467. The threonine at codon 823 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	0.69
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.41
MutPred		0.53		Gain of catalytic residue at P822 (P = 0.0275);.;.;
MVP		0.94
MPC		1.0
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.92
gMVP		0.76

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: chr16-68867220;