16-68833484-C-T

Variant names:

• chr16-68833484-C-T
• rs2229044
• NM_004360.5:c.2634C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.2634C>T (p.Gly878=) variant has an allele frequency of 0.03601 (3.6%, 899/24962 alleles, 20 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, 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, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA168961/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.016 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (139 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:20
• Conservation: PhyloP100: -4.03

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 Benign. Variant got -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2634C>T	p.Gly878Gly	synonymous_variant	Exon 16 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2451C>T	p.Gly817Gly	synonymous_variant	Exon 15 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.1086C>T	p.Gly362Gly	synonymous_variant	Exon 16 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.669C>T	p.Gly223Gly	synonymous_variant	Exon 15 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2634C>T	p.Gly878Gly	synonymous_variant	Exon 16 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2422 AN: 152036 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00595

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.00919 AC: 2311 AN: 251410 Hom.: 42 AF XY: 0.00850 AC XY: 1155 AN XY: 135878

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00513

Gnomad NFE exome AF: 0.00743

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.00751 AC: 10977 AN: 1461474 Hom.: 139 Cov.: 32 AF XY: 0.00741 AC XY: 5385 AN XY: 727038

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.00968

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.00498

Gnomad4 NFE exome AF: 0.00635

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0159 AC: 2424 AN: 152154 Hom.: 37 Cov.: 32 AF XY: 0.0156 AC XY: 1159 AN XY: 74388

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00595

Gnomad4 NFE AF: 0.00690

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0107 Hom.: 16

Bravo AF: 0.0181

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary diffuse gastric adenocarcinoma Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1; BP2_Strong (PMID: 30311375) -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Nov 18, 2014

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. -

Dec 01, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 02, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of prostate Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Aug 10, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_004360.5(CDH1):c.2634C>T (p.Gly878=) variant has an allele frequency of 0.03601 (3.6%, 899/24962 alleles, 20 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, 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, BP2. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 p.Gly878= variant was identified in 7 of 438 proband chromosomes (frequency: 0.02) from individuals or families with hereditary diffuse gastric cancer (Jakubowska 2010, Oliveira 2002, Guindalini 2019, El-Husny 2014). The variant was also identified in dbSNP (ID: rs2229044) as "With other allele" and ClinVar (classified as benign by Invitae, Ambry Genetics and two other submitters; and as likely benign by three submitters). The variant was identified in control databases in 2637 of 277164 chromosomes (47 homozygous) at a frequency of 0.009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 851 of 24030 chromosomes (freq: 0.04), Other in 122 of 6468 chromosomes (freq: 0.02), Latino in 430 of 34420 chromosomes (freq: 0.01), European in 911 of 126668 chromosomes (freq: 0.007), Ashkenazi Jewish in 112 of 10152 chromosomes (freq: 0.01), East Asian in 1 of 18864 chromosomes (freq: 0.00005), Finnish in 137 of 25780 chromosomes (freq: 0.005), and South Asian in 73 of 30782 chromosomes (freq: 0.002). The p.Gly878= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.6
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2229044; hg19: chr16-68867387; COSMIC: COSV55731553;