16-68822190-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_004360.5(CDH1):c.1901C>T(p.Ala634Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.58

Variant links:

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 links:

ENSG00000260798 (HGNC:):

ENSG00000260798 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-68822190-C-T is Pathogenic according to our data. Variant chr16-68822190-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68822190-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.1901C>T	p.Ala634Val	missense_variant	Exon 12 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.1718C>T	p.Ala573Val	missense_variant	Exon 11 of 15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.353C>T	p.Ala118Val	missense_variant	Exon 12 of 16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.-65C>T		5_prime_UTR_variant	Exon 11 of 15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.1901C>T	p.Ala634Val	missense_variant	Exon 12 of 16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000457

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Pathogenic:4

Jun 14, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12096341, 12588804, 17510211]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12588804, 15288293, 17545690, 20719348]. -

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong; PS3; PS4; PM2; PP1_Strong (PMID: 30311375) -

Mar 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 634 of the CDH1 protein (p.Ala634Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diffuse gastric cancer (DGC) (PMID: 12588804, 15288293, 15735979, 17221870, 17545690, 24493355, 29454568). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12244). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 12588804, 14500541, 17510211, 22850631, 25388006). Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 34503274; internal data). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Oct 04, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant causes a C>T nucleotide substitution at codon 634, predicted to create a cryptlc splice donor site in exon 12. RNA studies have reported the variant caused a deletion of 37 bases from exon 12 resulting in a premature termination codon (PMID: 12096341, 34503274). A mutant protein harboring this missense variant has shown decreased cell adhesion and increases in cell motility and invasion (PMID: 12588804, 22850631, 25388006). This variant has been reported in multiple diagnosed and suspected hereditary diffuse gastric cancer families (PMID: 12588804, 15288293, 15735979, 17221870, 17545690, 20719348, 24493355, 30014492, 34503274), including one family in which multiple members showed segregation of variant with disease (PMID: 29454568). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Jan 27, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A634V pathogenic mutation (also known as c.1901C>T) is located in coding exon 12 of the CDH1 gene. This alteration results from a C to T substitution at nucleotide position 1901. The alanine at codon 634 is replaced by valine, an amino acid with similar properties. This alteration has been reported in multiple families meeting clinical diagnosis of hereditary diffuse gastric cancer (HDGC) (Suriano G et al. Hum Mol Genet. 2003 Mar 1;12(5):575-82; Kaurah P et al. JAMA. 2007 Jun 6;297(21):2360-72; Molinaro V et al. Genes Chromosomes Cancer. 2014 May;53(5):432-45; More H. et al Hum Mutat. 2007 Feb;28(2):203). It was demonstrated to segregate with diffuse gastric cancer and lobular breast cancer in multiple individuals in a family with early-onset disease (Gullo I et al. Gastrointest. Endosc. 2018 Jun;87(6):1566-1575). In addition, this alteration was demonstrated to cause abnormal splicing in a colon cancer cell line (Vécsey-Semjén B et al. Oncogene. 2002 Jul;21(30):4646-62). Internal RNA studies have confirmed that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dec 09, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate (RNA), PS4, PP1_strong, PM2_Supporting c.1901C>T, located in exon 12 of the CDH1 gene, is predicted to result in the substitution of alanine to valine at codon 634, p.(Ala634Val),but the SpliceAI algorithm predicts a possible effect on splicing (0.91), aprobably abolishing the canonical donor site and causing the use of a new cryptic splice site. Experimental studies evidenced that this variant affects mRNA splicing (r.1900_1936del; p.Ala634Profs*7)(PMID: 12096341)(PVS1_Moderate (RNA)). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). In addition, it has been reported in ClinVar (6x as pathogenic, 2x as likely pathogenic) and in LOVD (3x pathogenic, 2x VUS) databases. This variant has been published several times in association with familial difuse gàstric cancer and co-segregates in multiple affected individuals (PMID: 17545690, PMID: 29454568, PMID: 34503274)(PP1_Strong, PS4). Based on currently available information, the variant c.1901C>T is classified as a pathogenic variant according to ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1. -

not provided

Pathogenic:1

May 03, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Pathogenic:1

Oct 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH1 c.1901C>T (p.Ala634Val) results in a non-conservative amino acid change located in the Cadherin domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: four predict the variant creates a cryptic 5 prime donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Kaurah_2007). The variant was absent in 251464 control chromosomes. c.1901C>T has been reported in the literature in multiple individuals affected with Breast Cancer or Gastric Cancer (e.g. Kaurah_2007, Gullo_2018). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.

Eigen

Benign

-0.0029

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;.;N

REVEL

Benign

0.11

Sift

Benign

0.67

T;.;T

Sift4G

Benign

0.84

T;T;T

Polyphen

0.051

B;.;.

Vest4

0.24

MutPred

0.36

Gain of sheet (P = 0.0344);.;.;

MVP

0.82

MPC

0.25

ClinPred

0.70

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.91

Position offset: -2

DS_DL_spliceai

0.53

Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over