NM_004360.5:c.84C>T

Variant names:

• chr16-68738332-C-T
• rs587780789
• NM_004360.5:c.84C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_004360.5(CDH1):​c.84C>T​(p.Cys28Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,536,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0540
• Publications: 2 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

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

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-68738332-C-T is Benign according to our data. Variant chr16-68738332-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.054 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.84C>T	p.Cys28Cys	synonymous_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.84C>T	p.Cys28Cys	synonymous_variant	Exon 2 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1532C>T		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1736C>T		5_prime_UTR_variant	Exon 2 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.84C>T	p.Cys28Cys	synonymous_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.84C>T	p.Cys28Cys	synonymous_variant	Exon 2 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.84C>T		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.84C>T		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.0000351 AC: 5 AN: 142572 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000468

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000256 AC: 4 AN: 156368 AF XY: 0.0000364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000496

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000118 AC: 164 AN: 1393836 Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 84 AN XY: 687384

African (AFR) AF: 0.0000318 AC: 1 AN: 31424

American (AMR) AF: 0.00 AC: 0 AN: 35076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25080

East Asian (EAS) AF: 0.00 AC: 0 AN: 35458

South Asian (SAS) AF: 0.00 AC: 0 AN: 78300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.000151 AC: 162 AN: 1076018

Other (OTH) AF: 0.0000173 AC: 1 AN: 57732

GnomAD4 genome AF: 0.0000351 AC: 5 AN: 142572 Hom.: 0 Cov.: 32 AF XY: 0.0000143 AC XY: 1 AN XY: 69736

African (AFR) AF: 0.0000523 AC: 2 AN: 38254

American (AMR) AF: 0.00 AC: 0 AN: 14516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3264

East Asian (EAS) AF: 0.00 AC: 0 AN: 4740

South Asian (SAS) AF: 0.00 AC: 0 AN: 4464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000468 AC: 3 AN: 64124

Other (OTH) AF: 0.00 AC: 0 AN: 1874

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH1 c.84C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.00e-05 within Non-Finnish European control individuals (i.e. 4/57386 control chromosomes) in the gnomAD database, which is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.84C>T in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Jul 01, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary diffuse gastric adenocarcinoma Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary cancer-predisposing syndrome Benign:2

Aug 03, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Mar 28, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDH1 c.84C>T; p.Cys28Cys variant (rs587780789), to our knowledge, is not reported in the medical literature but is reported as likely benign in ClinVar (Variation ID: 136070). This variant is found in the general population with an overall allele frequency of 0.003% (4/149530 alleles) in the Genome Aggregation Database. This is a synonymous change, the nucleotide is weakly conserved, and computational algorithms do not predict this variant to impact splicing (Alamut v.2.10). Based on available information, this variant is considered to be likely benign. -

Familial cancer of breast;C0376358:Prostate cancer;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1

Dec 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 09, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.7
DANN	Benign	0.89
PhyloP100		-0.054
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587780789; hg19: chr16-68772235;