rs1060501246

Positions:

• chr16-68808819-C-A
• chr16-68808819-C-G
• chr16-68808819-C-T

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.658C>A​(p.Leu220Met) 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 (★★).

• 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: 1.57

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 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.658C>A	p.Leu220Met	missense_variant	5/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.658C>A	p.Leu220Met	missense_variant	5/15		NP_001304113.1
CDH1	NM_001317185.2	c.-958C>A		5_prime_UTR_variant	5/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1162C>A		5_prime_UTR_variant	5/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.658C>A	p.Leu220Met	missense_variant	5/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Sep 03, 2023

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 220 of the CDH1 protein (p.Leu220Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 406666). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Jan 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Uncertain	0.43	T;T;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;.;.;.;N
REVEL	Uncertain	0.62
Sift	Benign	0.17	T;.;.;.;T
Sift4G	Benign	0.090	T;D;T;D;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.78
MutPred		0.82		Gain of catalytic residue at V216 (P = 0.0457);Gain of catalytic residue at V216 (P = 0.0457);Gain of catalytic residue at V216 (P = 0.0457);Gain of catalytic residue at V216 (P = 0.0457);Gain of catalytic residue at V216 (P = 0.0457);
MVP		0.83
MPC		0.89
ClinPred		0.98	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.42

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: rs1060501246; hg19: chr16-68842722;