rs116542018

Positions:

• chr16-68801830-A-G
• chr16-68801830-A-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.324A>G (p.Arg108=) variant has an allele frequency of 0.00769 (0.769%, 192/24966 alleles) in the African subpopulation and one homozygote in the European (Non-Finnish) 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/CA290000/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:21
• Conservation: PhyloP100: -0.0340

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.324A>G	p.Arg108=	synonymous_variant	3/16	ENST00000261769.10
CDH1	NM_001317184.2	c.324A>G	p.Arg108=	synonymous_variant	3/15
CDH1	NM_001317185.2	c.-1292A>G		5_prime_UTR_variant	3/16
CDH1	NM_001317186.2	c.-1496A>G		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.324A>G	p.Arg108=	synonymous_variant	3/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152176 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00741

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000900 AC: 226 AN: 251232 Hom.: 1 AF XY: 0.000641 AC XY: 87 AN XY: 135768

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000831

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000394 AC: 576 AN: 1461880 Hom.: 2 Cov.: 32 AF XY: 0.000353 AC XY: 257 AN XY: 727242

Gnomad4 AFR exome AF: 0.00690

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152294 Hom.: 3 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74474

Gnomad4 AFR AF: 0.00746

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00110 Hom.: 1

Bravo AF: 0.00272

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 29, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 20, 2021	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2016	Variant summary: Variant Summary: The c.324G>A (p.Arg108=) in CDH1 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 3/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.1% (126/121336 chrs tested), mainly in individuals of African descent (0.83%; 86/10384 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic CDH1 variant (0.0028%), suggesting that it is a common polymorphism. Based on the published reports, the variant of interest was found in affected individuals as well as in unaffected controls. Lastly, the variant has been reported as Benign by multiple reputable database/clinical laboratories. Taken together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CDH1: BP4, BP7, BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

Hereditary diffuse gastric adenocarcinoma Benign:2

Benign, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	BA1; BS2; BP2_Strong (PMID: 30311375) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 27, 2023

- -

Malignant tumor of prostate Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CDH1 p.Arg108= variant was identified in 3 of 594 proband chromosomes (frequency: 0.005) from Canadian and Brazilian individuals or families with early-onset gastric cancer or nonsyndromic orofacial cleft (reportedly associated with gastric cancer), and in 6 of 1218 chromosomes (frequency: 0.005) from healthy individuals (Bacani_2006_16801346, Brito_2015_26123647, ). The variant was also identified in dbSNP (ID: rs116542018) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Invitae and EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), and likely benign by Ambry Genetics), Clinvitae (4x), Insight Colon Cancer Gene Variant Database (2x), and in control databases in 288 (1 homozygous) of 276950 chromosomes at a frequency of 0.001 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 187 of 24030 chromosomes (freq: 0.008), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 32 of 34418 chromosomes (freq: 0.0009), European Non-Finnish in 43 (1 homozygous) of 126460 chromosomes (freq: 0.0003), East Asian in 1 of 18866 chromosomes (freq: 0.00005), European Finnish in 20 of 25792 chromosomes (freq: 0.0008), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while not observed in the Ashkenazi Jewish population. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The p.Arg108= 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 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. -

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 10, 2023

The NM_004360.5(CDH1):c.324A>G (p.Arg108=) variant has an allele frequency of 0.00769 (0.769%, 192/24966 alleles) in the African subpopulation and one homozygote in the European (Non-Finnish) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.7
DANN	Benign	0.57

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: rs116542018; hg19: chr16-68835733;