rs16260

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 206 publications found

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]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for CDH1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.-285C>A		upstream_gene	N/A	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.-285C>A		upstream_gene	N/A	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.-1900C>A		upstream_gene	N/A	NP_001304114.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.-285C>A		upstream_gene	N/A	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.-285C>A		upstream_gene	N/A	ENSP00000414946.2	P12830-2
	CDH1	ENST00000566612.5	TSL:1	n.-285C>A		upstream_gene	N/A	ENSP00000454782.1	H3BNC6

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

African (AFR) AF: 0.156 AC: 1240 AN: 7928

American (AMR) AF: 0.280 AC: 3852 AN: 13740

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 4594 AN: 11958

East Asian (EAS) AF: 0.203 AC: 5170 AN: 25518

South Asian (SAS) AF: 0.241 AC: 9191 AN: 38184

European-Finnish (FIN) AF: 0.238 AC: 6712 AN: 28238

Middle Eastern (MID) AF: 0.314 AC: 563 AN: 1794

European-Non Finnish (NFE) AF: 0.281 AC: 67835 AN: 241330

Other (OTH) AF: 0.281 AC: 6561 AN: 23372

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

African (AFR) AF: 0.160 AC: 6639 AN: 41546

American (AMR) AF: 0.287 AC: 4390 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1372 AN: 3472

East Asian (EAS) AF: 0.279 AC: 1438 AN: 5154

South Asian (SAS) AF: 0.249 AC: 1200 AN: 4820

European-Finnish (FIN) AF: 0.237 AC: 2507 AN: 10594

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19051 AN: 67970

Other (OTH) AF: 0.257 AC: 543 AN: 2114

Alfa AF: 0.272 Hom.: 10968

Bravo AF: 0.246

Asia WGS AF: 0.293 AC: 1017 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	-	1	Hereditary diffuse gastric adenocarcinoma (1)
-	-	1	Prostate cancer susceptibility (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.9
DANN	Benign	0.71
PhyloP100		-0.022
PromoterAI		0.018	Neutral

Splicing

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

Other links and lift over

dbSNP: rs16260; hg19: chr16-68771034;