16-68823386-T-C

Variant names:

• chr16-68823386-T-C
• rs2276330
• NM_004360.5:c.1937-13T>C

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.1937-13T>C variant has an allele frequency of 0.16607 (16.6%, 4107/24730 alleles, 330 homozygotes) in the European (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/CA163616/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.095 (871 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11676 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:15
• Conservation: PhyloP100: 0.184

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.1937-13T>C		intron_variant	Intron 12 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1754-13T>C		intron_variant	Intron 11 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.389-13T>C		intron_variant	Intron 12 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-29-13T>C		intron_variant	Intron 11 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1937-13T>C		intron_variant	Intron 12 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0949 AC: 14433 AN: 152152 Hom.: 872 Cov.: 31

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0705

Gnomad SAS AF: 0.0536

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.0920

GnomAD3 exomes AF: 0.103 AC: 25875 AN: 250252 Hom.: 1597 AF XY: 0.105 AC XY: 14188 AN XY: 135466

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.0476

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.0795

Gnomad SAS exome AF: 0.0537

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.122 AC: 173911 AN: 1429786 Hom.: 11676 Cov.: 27 AF XY: 0.120 AC XY: 85559 AN XY: 713624

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.0497

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0544

Gnomad4 SAS exome AF: 0.0543

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.0948 AC: 14431 AN: 152270 Hom.: 871 Cov.: 31 AF XY: 0.0932 AC XY: 6938 AN XY: 74444

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.0665

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0709

Gnomad4 SAS AF: 0.0536

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.0915

Alfa AF: 0.122 Hom.: 1841

Bravo AF: 0.0869

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

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

- -

Hereditary diffuse gastric adenocarcinoma Benign:4

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. -

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 intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

- -

not provided Uncertain:1 Benign:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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: 24204729) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:2

Dec 19, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 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. -

Prostate cancer Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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_004360.5(CDH1):c.1937-13T>C variant has an allele frequency of 0.16607 (16.6%, 4107/24730 alleles, 330 homozygotes) in the European (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	-0.83
CADD	Benign	9.0
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2276330; hg19: chr16-68857289; COSMIC: COSV55727021; COSMIC: COSV55727021;