rs33963999

Variant names:

• chr16-68808577-G-C
• rs33963999
• NM_004360.5:c.531+10G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-68808577-G-C
• chr16-68808577-G-T

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.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 homozygotes) in the African 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/CA169542/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.038 (175 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2440 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Benign reviewed by expert panel B:18
• Conservation: PhyloP100: 0.855

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.531+10G>C		intron_variant	Intron 4 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.531+10G>C		intron_variant	Intron 4 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1085+10G>C		intron_variant	Intron 4 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1289+10G>C		intron_variant	Intron 4 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.531+10G>C		intron_variant	Intron 4 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5790 AN: 152172 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.0430

GnomAD3 exomes AF: 0.0385 AC: 9672 AN: 251068 Hom.: 254 AF XY: 0.0391 AC XY: 5312 AN XY: 135756

Gnomad AFR exome AF: 0.00910

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.0586

Gnomad NFE exome AF: 0.0546

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0538 AC: 78655 AN: 1461656 Hom.: 2440 Cov.: 33 AF XY: 0.0527 AC XY: 38312 AN XY: 727122

Gnomad4 AFR exome AF: 0.00833

Gnomad4 AMR exome AF: 0.0237

Gnomad4 ASJ exome AF: 0.0396

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.0600

Gnomad4 NFE exome AF: 0.0612

Gnomad4 OTH exome AF: 0.0493

GnomAD4 genome AF: 0.0380 AC: 5792 AN: 152290 Hom.: 175 Cov.: 32 AF XY: 0.0381 AC XY: 2840 AN XY: 74464

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.0319

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.0536

Gnomad4 NFE AF: 0.0581

Gnomad4 OTH AF: 0.0425

Alfa AF: 0.0492 Hom.: 49

Bravo AF: 0.0343

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary diffuse gastric adenocarcinoma Benign:4

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

- -

Jan 13, 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 13, 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. -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Dec 10, 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. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

CDH1, EXON4, c.531+10G>C, p.?, Heterozygous, BenignrnThe CDH1 c.531+10G>C variant was identified in 7 of 194 proband chromosomes (frequency: 0.036) from individuals or families with gastric cancer and colorectal cancer, but the variant was classified as a benign polymorphism in these studies (Berx 1997, Oliveira 2002, Verma 2001). The variant was also identified in dbSNP (rs: rs33963999) as other, ClinVar 5x (classified as benign by multiple submitters), and the Zhejiang Colon Cancer Database (3x). The variant was not identified in Cosmic, MutDB, or Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 10752 of 276938 chromosomes at a frequency of 0.0388 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Finnish) in 1496 (42 homozygous) of 25776 chromosomes (freq: 0.058), European (Non-Finnish) in 6956 (196 homozygous) of 126510 chromosomes (freq: 0.055), Ashkenazi Jewish* in 404 (11 homozygous) of 10146 chromosomes (freq: 0.04), Other in 245 (8 homozygous) of 6458 chromosomes (freq: 0.038), Latino in 750 (13 homozygous) of 34410 chromosomes (freq: 0.022), South Asian in 665 (12 homozygous) of 30780 chromosomes (freq: 0.022). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Malignant tumor of prostate 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.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 homozygotes) in the African 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	-0.80
CADD	Benign	13
DANN	Benign	0.55

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: rs33963999; hg19: chr16-68842480; COSMIC: COSV55728473; COSMIC: COSV55728473;