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

Scores

9
8
2

Clinical Significance

Likely benign reviewed by expert panel U:6B:6O:1

Conservation

PhyloP100: 5.08
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDH1NM_004360.5 linkuse as main transcriptc.1225T>C p.Trp409Arg missense_variant 9/16 ENST00000261769.10
CDH1NM_001317185.2 linkuse as main transcriptc.-391T>C 5_prime_UTR_variant 9/16
CDH1NM_001317186.2 linkuse as main transcriptc.-595T>C 5_prime_UTR_variant 9/15
CDH1NM_001317184.2 linkuse as main transcriptc.1137+1137T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.1225T>C p.Trp409Arg missense_variant 9/161 NM_004360.5 P1P12830-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152058
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:6Benign:6Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 05, 2023This 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 submittercurationSema4, Sema4Mar 04, 2022- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 17, 2020This 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 submitterclinical testingGeneDxJul 20, 2017This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 01, 2016Variant 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -
Likely benign, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalSep 10, 2020The 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 submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioSep 22, 2022- -
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 08, 2022- -
CDH1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 16, 2020This 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 panelcurationClinGen CDH1 Variant Curation Expert PanelAug 17, 2023The 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 providedreference populationITMISep 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

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

Other links and lift over

dbSNP: rs587778176; hg19: chr16-68847303; API