rs1801023

Positions:

• chr16-68801851-G-A
• chr16-68801851-G-C
• chr16-68801851-G-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 c.345G>A variant has an allele frequency of 0.007677 (0.77%, 235/30,612 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD 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/CA293902/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (25 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:21
• Conservation: PhyloP100: -5.60

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.345G>A	p.Thr115=	synonymous_variant	3/16	ENST00000261769.10
CDH1	NM_001317184.2	c.345G>A	p.Thr115=	synonymous_variant	3/15
CDH1	NM_001317185.2	c.-1271G>A		5_prime_UTR_variant	3/16
CDH1	NM_001317186.2	c.-1475G>A		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.345G>A	p.Thr115=	synonymous_variant	3/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00372 AC: 933 AN: 251082 Hom.: 5 AF XY: 0.00417 AC XY: 566 AN XY: 135694

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00768

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00414

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00373 AC: 5456 AN: 1461852 Hom.: 25 Cov.: 32 AF XY: 0.00383 AC XY: 2786 AN XY: 727222

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00976

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00827

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00362

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00282 AC XY: 210 AN XY: 74466

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00388

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00357 Hom.: 1

Bravo AF: 0.00250

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00533

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:10

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2013	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. -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 09, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary diffuse gastric adenocarcinoma Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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; BP2_Strong (PMID: 30311375) -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 13, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2014	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CDH1: BP4, BP7, BS2 -

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 c.345G>A variant has an allele frequency of 0.007677 (0.77%, 235/30,612 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD 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 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.Thr115Thr variant was identified in 6 of 380 proband chromosomes (frequency: 0.016) from individuals or families with gastric cancer, other cancer types and normal individuals (Garziera 2013) and was present in 1 of 40 control chromosomes (frequency: 0.025) from healthy individuals (Berx 1997). The variant was also identified in dbSNP (ID: rs1801023) as “With other allele”, ClinVar (6x, as benign by Invitae, GeneDx, Ambry Genetics, Prevention Genetics, Color Genomics, as likely benign by Illumina), Clinvitae (3x as benign ), Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 991 of 276784 (5 homozygous) chromosomes at a frequency of 0.0036 in the following populations: African in 12 of 24020 chromosomes (freq. 0.0005), other in 26 of 6460 chromosomes (freq. 0.004), Latino in 72 of 34410 chromosomes (freq. 0.002), European in 518 of 126334 chromosomes (freq. 0.0041), Ashkenazi Jewish in 109 of 10130 chromosomes (freq. 0.01), East Asian in 3 of 18868 chromosomes (freq. 0.00016), Finnish in 15 of 25784 chromosomes (freq. 0.0006), and South Asian in 236 of 30778 chromosomes (freq. 0.0076),.increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr115Thr 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.47
DANN	Benign	0.58

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: rs1801023; hg19: chr16-68835754; COSMIC: COSV104558511;