16-68819394-G-C

Variant names:

• chr16-68819394-G-C
• rs35741240
• NM_004360.5:c.1680G>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004360.5(CDH1):​c.1680G>C​(p.Thr560Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,613,740 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (26 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: -3.61

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]

ENSG00000260798 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-68819394-G-C is Benign according to our data. Variant chr16-68819394-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 136697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68819394-G-C is described in Lovd as [Likely_benign]. Variant chr16-68819394-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00261 (398/152234) while in subpopulation SAS AF= 0.00519 (25/4816). AF 95% confidence interval is 0.00361. There are 0 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1680G>C	p.Thr560Thr	synonymous_variant	Exon 11 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1497G>C	p.Thr499Thr	synonymous_variant	Exon 10 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.132G>C	p.Thr44Thr	synonymous_variant	Exon 11 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-254-2607G>C		intron_variant	Intron 10 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1680G>C	p.Thr560Thr	synonymous_variant	Exon 11 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00337 AC: 848 AN: 251482 Hom.: 4 AF XY: 0.00386 AC XY: 524 AN XY: 135914

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00686

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00352 AC: 5151 AN: 1461506 Hom.: 26 Cov.: 32 AF XY: 0.00366 AC XY: 2662 AN XY: 727044

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00698

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00373

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74422

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00272 Hom.: 0

Bravo AF: 0.00223

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:29

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:9

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 p.Thr560= variant was identified in the literature in 1 of 20 normal chromosomes (frequency: 0.025); however the frequency of this variant in an affected population was not provided (Berx 1997). The variant was also identified in dbSNP (ID: rs35741240) as “With Likely benign, other allele”, in the ClinVar database as benign by GeneDx, Ambry Genetics, EGL Genetic Diagnostics, Invitae, ARUP Laboratories and as likely benign by Illumina Clinical Services; in the Clinvitae database as benign by EmyClass; and in the Cosmic and in Zhejiang Colon Cancer Databases 1X in haemangioblastoma. The variant was not identified in MutDB or the Insight Colon Cancer Gene Variant databases. The variant was further identified in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002) and in the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and 3 in 4396 in African American alleles. The variant was identified in control databases in 925 of 277220 chromosomes (4 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 19 of 24022 chromosomes (freq: 0.0008), other in 14 of 6464 chromosomes (freq: 0.002), Latino in 46 of 34420 chromosomes (freq: 0.001), European Non-Finnish in 573 of 126722 chromosomes (freq: 0.004), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), East Asian in 2 of 18868 chromosomes (freq: 0.0001), European Finnish in 52 of 25794 chromosomes (freq: 0.002), and South Asian in 211 of 30778 chromosomes (freq: 0.007). The p.Thr560= 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, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH1: BP4, BP7, BS2 -

not specified Benign:7

Jan 06, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary diffuse gastric adenocarcinoma Benign:7

Jan 04, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH1 p.T560T (NM_004360.3:c.1680G>C) has been reported at a frequency of approximately 1 in 100 individuals of European ancestry (exac.broadinstitute.org). This variant frequency is too high to be consistent with the cancer risk syndrome seen with pathogenic CDH1 variants (Hansford 2015). This evidence supports classification of this variant as likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. -

Sep 19, 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. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

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) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Aug 15, 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. -

Apr 07, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Benign:1

Jun 12, 2023

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0040
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35741240; hg19: chr16-68853297; COSMIC: COSV55731541; COSMIC: COSV55731541;