16-68822190-C-T

Variant names:

• chr16-68822190-C-T
• rs121964878
• NM_004360.5:c.1901C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM2 PP3_Moderate PP5_Very_Strong BS2_Supporting

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A634E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.58
• Publications: 59 publications found

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 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 12244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.1901C>T	p.Ala634Val	missense	Exon 12 of 16	NP_004351.1
	CDH1	NM_001317184.2		c.1718C>T	p.Ala573Val	missense	Exon 11 of 15	NP_001304113.1
	CDH1	NM_001317185.2		c.353C>T	p.Ala118Val	missense	Exon 12 of 16	NP_001304114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1901C>T	p.Ala634Val	missense	Exon 12 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.1718C>T	p.Ala573Val	missense	Exon 11 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.1972C>T		non_coding_transcript_exon	Exon 11 of 15

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000284 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:5

Apr 15, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

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.

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].

Mar 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hereditary cancer-predisposing syndrome Pathogenic:3

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.

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.

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.0029
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.67	T
Sift4G	Benign	0.84	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	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.37
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs121964878; hg19: chr16-68856093; COSMIC: COSV55730231; COSMIC: COSV55730231;