rs587778176

Positions:

• chr16-68813400-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.1225T>C (p. Trp409Arg) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157989/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:6 B:6 O:1
• Conservation: PhyloP100: 5.08

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_benign. Variant got -4 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1225T>C	p.Trp409Arg	missense_variant	9/16	ENST00000261769.10
CDH1	NM_001317185.2	c.-391T>C		5_prime_UTR_variant	9/16
CDH1	NM_001317186.2	c.-595T>C		5_prime_UTR_variant	9/15
CDH1	NM_001317184.2	c.1137+1137T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1225T>C	p.Trp409Arg	missense_variant	9/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251486 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74244

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6 Benign:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces tryptophan with arginine at codon 409 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting findings on variant impact on cell adhesion (PMID: 15235021, 27582386). This variant has been reported in an individual affected with diffused gastric cancer (PMID: 15235021) and an individual affected with stomach cancer (PMID: 19269290). In a large breast cancer case-control study, the variant has been reported in 0/60466 cases and 2/53461 unaffected controls (PMID: 33471991). It has also been reported as observed in more than 10 individuals without personal or family history of gastric cancer with signet ring cell morphology or lobular breast cancer (ClinVar variation ID: 133855). This variant has been identified in 5/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available data indicate this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2017	This variant is denoted CDH1 c.1225T>C at the cDNA level, p.Trp409Arg (W409R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG). This variant was observed in an individual with diffuse gastric cancer and a family history of signet ring colon cancer (Brooks-Wilson 2004). Studies assessing the functional impact of this variant have found discordant results. While Brooks-Wilson et al. (2004) reported abnormal cell-cell adhesion and collagen invasion on in vitro assays, Petrova et al. (2016) identified cell-cell adhesion and aggregation comparable to wild-type. CDH1 Trp409Arg was also identified in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. CDH1 Trp409Arg was observed at an allele frequency of 0.006% (4/66740) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Trp409Arg occurs at a position that is conserved through mammals and is located in Cadherin 3 of the extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDH1 Trp409Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 01, 2016	Variant summary: The CDH1 c.1225T>C (p.Trp409Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools utilized predict a damaging outcome for this variant. The residue W409 is found in the third calcium binding domain of the E-cadherin protein at EC2-3 junction, adjacent residue from calcium binding site (Brooks-Wilson_2004, Lee_2014). Consistent with these findings, an in vitro functional study showedthe variant to impact CDH1 functionality by the variant (Brooks-Wilson_2004). This variant was found in 4/121412 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000599 (4/66740 chromosomes). This frequency is about 2.87 times higher than the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000208), suggesting this variant may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, as CDH1 linked phenotypes (HDGC and HBOC) have generally late-onset (average age of onset >35 years), four individuals with the variant in ExAC may represent reduced penetrance or subclinical cases. This germline variant has been reported in literature in one isolated HDGC patient who also had signet ring cell cancer of the colon (Brooks-Wilson_2004). The patient was also characterized to have promoter methylation + loss of heterozygosity and genotype was considered to be consistent with the phenotype in the patient (Oliveira_2009). Multiple clinical diagnostic laboratories have databases classified this variant as uncertain significance. Taken together, primarily due to some conflicts about pathogenicity of the variant, it is currently classified as Variant of Unknown Significance. -

Hereditary diffuse gastric adenocarcinoma Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 10, 2020	The c.1225T>C (p. Trp409Arg) missense variant has a frequency of 0.00002 (5 of 251,486 alleles) in gnomAD, with a maximum allele frequency of 0.00004 (5 of 113,762) in the Non-Finnish European subpopulation (http://gnomad.broadinstitute.org). Although this variant was reported in an individual with diffuse gastric cancer and a family history of signet ring colon cancer (PMID: 15235021), these diagnoses do not meet clinical criteria for hereditary diffuse gastric cancer (PMID: 32758476). Data submitted to the ClinGen CDH1 variant curation expert panel indicates that this variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring cell tumors or lobular breast cancer and whose families do not suggest hereditary diffuse gastric cancer (BS2). Six of seven in silico tools predict a deleterious effect of this variant on protein function. While Brooks-Wilson et al. (PMID: 15235021) reported abnormal cell-cell adhesion and collagen invasion on in vitro assays, Petrova et al. (PMID: 26175155) identified cell-cell adhesion and aggregation comparable to wild-type. As the CDH1 variant curation expert panel only approves the use of assays that measure abnormal splicing of the CDH1 gene, functional data was not utilized as evidence of pathogenicity (PMID: 30311375). This variant has been called likely benign by the ClinGen CDH1 Variant Curation Expert Panel (SCV000864607.3). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 2): BS2. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 22, 2022

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CDH1 p.Trp409Arg variant was identified in 2 of 1448 proband chromosomes (frequency: 0.001) from individuals or families with gastric cancer (Bodian 2014, Brooks-Wilson 2004). The variant was also identified in the following databases: dbSNP (ID: rs587778176) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics, LCOA clinical laboratory), and Clinvitae. The variant was not identified in Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 5 of 246262 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population: in 5 of 111712 chromosomes (freq: 0.0001); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant is found in the third calcium binding domain of the E-cadherin protein and has been shown to lead to loss-of-function in vitro and increased pathogenicity in vivo (Brooks-Wilson 2004, Simoes_Correia 2012). Another functional assay by Petrova (2016) displayed that the variant has no detectable effect on adhesion activation and behaves like WT E-cadherin under various drug treatments. The p.Trp409 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

CDH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.1225T>C (p. Trp409Arg) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.8	H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-13	D;.;.;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.87
MutPred		0.84		Loss of catalytic residue at A408 (P = 0.0165);Loss of catalytic residue at A408 (P = 0.0165);Loss of catalytic residue at A408 (P = 0.0165);Loss of catalytic residue at A408 (P = 0.0165);
MVP		0.89
MPC		1.2
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.81
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587778176; hg19: chr16-68847303;