rs1801552

Variant names:

• chr16-68823538-T-C
• rs1801552
• NM_004360.5:c.2076T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-68823538-T-C
• chr16-68823538-T-G

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.2076T>C (p.Ala692=) variant has an allele frequency of 0.88894 (88.89%, 22156/24924 alleles, 9856 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2_Supporting). 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_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA169363/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.70 (38079 hom., cov: 30)
  • Exomes 𝑓: 0.64 (297080 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:23
• Conservation: PhyloP100: 0.0880

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]

ENSG00000260798 (HGNC:):

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.2076T>C	p.Ala692Ala	synonymous_variant	Exon 13 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1893T>C	p.Ala631Ala	synonymous_variant	Exon 12 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.528T>C	p.Ala176Ala	synonymous_variant	Exon 13 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.111T>C	p.Ala37Ala	synonymous_variant	Exon 12 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2076T>C	p.Ala692Ala	synonymous_variant	Exon 13 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106055 AN: 151870 Hom.: 38020 Cov.: 30

Gnomad AFR AF: 0.884

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.651 AC: 163615 AN: 251308 Hom.: 53968 AF XY: 0.645 AC XY: 87665 AN XY: 135836

Gnomad AFR exome AF: 0.891

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.631

Gnomad EAS exome AF: 0.650

Gnomad SAS exome AF: 0.653

Gnomad FIN exome AF: 0.592

Gnomad NFE exome AF: 0.625

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.635 AC: 928592 AN: 1461334 Hom.: 297080 Cov.: 47 AF XY: 0.634 AC XY: 461109 AN XY: 726980

Gnomad4 AFR exome AF: 0.895

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.607

Gnomad4 SAS exome AF: 0.649

Gnomad4 FIN exome AF: 0.596

Gnomad4 NFE exome AF: 0.628

Gnomad4 OTH exome AF: 0.651

GnomAD4 genome AF: 0.699 AC: 106179 AN: 151988 Hom.: 38079 Cov.: 30 AF XY: 0.696 AC XY: 51668 AN XY: 74270

Gnomad4 AFR AF: 0.884

Gnomad4 AMR AF: 0.653

Gnomad4 ASJ AF: 0.632

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.685

Alfa AF: 0.635 Hom.: 43730

Bravo AF: 0.711

Asia WGS AF: 0.711 AC: 2471 AN: 3478

EpiCase AF: 0.620

EpiControl AF: 0.620

ClinVar

Significance: Benign

Submissions summary: Benign:23

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

EXAC frequency 65% -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary diffuse gastric adenocarcinoma Benign:5

Sep 20, 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. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25648022, 24838934) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of prostate Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Aug 29, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Blepharocheilodontic syndrome 1 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Aug 09, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_004360.5(CDH1):c.2076T>C (p.Ala692=) variant has an allele frequency of 0.88894 (88.89%, 22156/24924 alleles, 9856 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2_Supporting). 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_Supporting. -

Familial cancer of breast Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: 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	-0.88
CADD	Benign	6.3
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1801552; hg19: chr16-68857441; COSMIC: COSV55728161; COSMIC: COSV55728161;