16-68812144-A-G

Variant names:

• chr16-68812144-A-G
• rs116093741
• NM_004360.5:c.1018A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.1018A>G (p.Thr340Ala) variant has an allele frequency of 0.00360 (0.36%, 68/18,866 alleles) in the East Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA288016/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:2 B:13
• Conservation: PhyloP100: -0.366
• Publications: 53 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1018A>G	p.Thr340Ala	missense	Exon 8 of 16	NP_004351.1
	CDH1	NM_001317185.2		c.-598A>G		5_prime_UTR_premature_start_codon_gain	Exon 8 of 16	NP_001304114.1
	CDH1	NM_001317186.2		c.-802A>G		5_prime_UTR_premature_start_codon_gain	Exon 8 of 15	NP_001304115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1018A>G	p.Thr340Ala	missense	Exon 8 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.1018A>G	p.Thr340Ala	missense	Exon 8 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.1089A>G		non_coding_transcript_exon	Exon 7 of 15

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152056 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: 0.00328

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000266 AC: 67 AN: 251482 AF XY: 0.000258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000903 AC: 132 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.000105 AC XY: 76 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00287 AC: 114 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111990

Other (OTH) AF: 0.000116 AC: 7 AN: 60392

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74410

African (AFR) AF: 0.00 AC: 0 AN: 41502

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00329 AC: 17 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:1 Benign:4

Mar 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1 (PMID: 30311375)

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1 Benign:2

Mar 26, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28389907, 22850631, 15457549, 25187893, 19268661, 12588804, 11968083, 10896919, 15235021, 21989054, 19725995, 12944922, 16501831, 25856671, 16600987, 25180051, 26072394, 27121310, 26822949, 25388006, 27582386, 28503720, 28522256, 29752822, 14500541, 28580595, 31350202, 32091409, 32426482, 32521533)

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 p.Thr340Ala variant was identified in 8 of 642 proband chromosomes (frequency: 0.01) from individuals or families with gastric and colorectal cancer and was not identified in 686 control chromosomes from healthy individuals (Kim 2000, Oliveira 2002, Zhang 2006, Chang 2016). The variant was also identified in dbSNP (ID: rs116093741) with "uncertain significance, other allele," ClinVar with conflicting interpretations (1x pathogenic: OMIM, literature only; 2x likely benign: Invitae, Illumina; 2x uncertain significance: GeneDx, Ambry Genetics), COSMIC (3x somatic status unknown: 1x alveolar soft part sarcoma, 2x carcinoma, described as a "likely passenger" mutation in a thyroid carcinoma, Sohn 2016), MutDB (MutPred very confident that the variant is disease associated), Zhejiang University Database (3x "probably pathogenic" in hereditary gastric cancer, Wang 2004, Mateus 2009, Suriano 2006). The variant was not identified in the Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 68 of 277198 chromosomes at a frequency of 0.0002; or in 68 of 18866 (freq:0.0036) East Asian individuals, increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Thr340Ala missense variant was shown by computer modelling to be located in a newly characterized E-cadherin sequence motif, likely to be involved in the stabilization of the active protein conformation (Suriano 2003). In various function studies the variant was concluded to be pathogenic conferring enhanced cell motility, disrupted cell adhesion, and loss of epithelial structure (Suriano 2003, Mateus 2009). The p.Thr340Ala residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.

Hereditary cancer-predisposing syndrome Benign:3

Feb 13, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 21, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

Apr 07, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gastric adenocarcinoma Uncertain:1

Nov 29, 2017

3DMed Clinical Laboratory Inc

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Feb 25, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH1 c.1018A>G (p.Thr340Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 277884 control chromosomes, predominantly at a frequency of 0.0036 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 127 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1018A>G has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer all of whom were of the same ethnic composition as seen in control databases . Therefore, these reports do not provide unequivocal evidence supporting a deleterious outcome. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing experience (BRCA1 c.188T>A, p.Leu63X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments ranging from likely benign (n=2) or VUS (n=3). Most recently, the Clingen CDH1 variant curation expert panel has classified this variant as benign based solely on its allele frequency in the East Asian population (ACMG, BA1). Based on the evidence outlined above, the variant was classified as benign.

Breast and/or ovarian cancer Benign:1

Apr 23, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH1-related disorder Benign:1

Apr 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 08, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.1018A>G (p.Thr340Ala) variant has an allele frequency of 0.00360 (0.36%, 68/18,866 alleles) in the East Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	5.1
DANN	Benign	0.59
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.82	L
PhyloP100		-0.37
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.29
Sift	Benign	0.046	D
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.60
MPC		0.25
ClinPred		0.016	T
GERP RS		-3.7
Varity_R		0.22
gMVP		0.27
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs116093741; hg19: chr16-68846047; COSMIC: COSV55732016;