16-68833553-C-T

Position:

• chr16-68833553-C-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.*54C>T variant has an allele frequency of 0.18763 (18.76%, 1629/8682 alleles, 147 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/CA10647973/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.17 (2099 hom., cov: 32)
  • Exomes 𝑓: 0.15 (15571 hom.)
• Consequence: CDH1 NM_004360.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -1.45

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.*54C>T		3_prime_UTR_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.*54C>T		3_prime_UTR_variant	15/15
CDH1	NM_001317185.2	c.*54C>T		3_prime_UTR_variant	16/16
CDH1	NM_001317186.2	c.*54C>T		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.*54C>T		3_prime_UTR_variant	16/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25367 AN: 151854 Hom.: 2090 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.0953

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.158

GnomAD4 exome AF: 0.152 AC: 196390 AN: 1295424 Hom.: 15571 Cov.: 18 AF XY: 0.149 AC XY: 97527 AN XY: 653218

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.0944

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.167 AC: 25417 AN: 151972 Hom.: 2099 Cov.: 32 AF XY: 0.166 AC XY: 12333 AN XY: 74248

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.0956

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.163

Alfa AF: 0.101 Hom.: 235

Bravo AF: 0.173

Asia WGS AF: 0.147 AC: 508 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21459793, 19563064, 21432908) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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.*54C>T variant has an allele frequency of 0.18763 (18.76%, 1629/8682 alleles, 147 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.77

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: rs1801026; hg19: chr16-68867456; COSMIC: COSV55730964; COSMIC: COSV55730964;