16-68833368-T-C

Position:

• chr16-68833368-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004360.5(CDH1):​c.2518T>C​(p.Ser840Pro) variant causes a missense change involving the alteration of a 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. S840S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.01

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 modified_residue Phosphoserine (size 0) in uniprot entity CADH1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2518T>C	p.Ser840Pro	missense_variant	16/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2335T>C	p.Ser779Pro	missense_variant	15/15		NP_001304113.1
CDH1	NM_001317185.2	c.970T>C	p.Ser324Pro	missense_variant	16/16		NP_001304114.1
CDH1	NM_001317186.2	c.553T>C	p.Ser185Pro	missense_variant	15/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2518T>C	p.Ser840Pro	missense_variant	16/16	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:3

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

May 07, 2022

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"). ClinVar contains an entry for this variant (Variation ID: 463767). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 840 of the CDH1 protein (p.Ser840Pro). -

Hereditary cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

This missense variant replaces serine with proline at codon 840 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;T;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.75
MutPred		0.79		Loss of phosphorylation at S840 (P = 0.0105);.;.;
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.95
gMVP		0.88

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: rs1555518243; hg19: chr16-68867271;