rs16260

Variant names:

• chr16-68737131-C-A
• rs16260
• NM_004360.5:c.-285C>A

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_004360.4(CDH1):c.-124-161C>A variant has an allele frequency of 0.27733 (27.73%, 4262/15368 alleles, 578 homozygotes) 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/CA122000/MONDO:0100488/007

• Frequency:
  • Genomes: 𝑓 0.25 (4868 hom., cov: 32)
  • Exomes 𝑓: 0.27 (14920 hom.)
• Consequence: CDH1 NM_004360.5 upstream_gene
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.0220

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.-285C>A		upstream_gene_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.-285C>A		upstream_gene_variant			NP_001304113.1
CDH1	NM_001317185.2	c.-1900C>A		upstream_gene_variant			NP_001304114.1
CDH1	NM_001317186.2	c.-2104C>A		upstream_gene_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.-285C>A		upstream_gene_variant		1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.-285C>A		upstream_gene_variant		1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.-285C>A		upstream_gene_variant		1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.-285C>A		upstream_gene_variant		5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37459 AN: 152044 Hom.: 4870 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.270 AC: 105718 AN: 392062 Hom.: 14920 AF XY: 0.270 AC XY: 55583 AN XY: 206134

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.384

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.281

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.246 AC: 37461 AN: 152162 Hom.: 4868 Cov.: 32 AF XY: 0.246 AC XY: 18294 AN XY: 74374

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.257

Alfa AF: 0.275 Hom.: 2700

Bravo AF: 0.246

Asia WGS AF: 0.293 AC: 1017 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23231047, 24491043, 11896626, 10706097, 24023817, 22792244, 17960397, 21997289, 19569232, 16189707, 22194161, 18781193, 21214416, 20462505, 17201188) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Prostate cancer susceptibility Benign:1

Dec 01, 2005

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary diffuse gastric adenocarcinoma Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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_004360.4(CDH1):c.-124-161C>A variant has an allele frequency of 0.27733 (27.73%, 4262/15368 alleles, 578 homozygotes) 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	-0.73
CADD	Benign	3.9
DANN	Benign	0.71

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16260; hg19: chr16-68771034;