NM_004360.5:c.2131C>G

Variant names:

• chr16-68823593-C-G
• rs121964871
• NM_004360.5:c.2131C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2131C>G variant is <1/50,000 alleles (0.002%, 2/128,916 alleles) in the non-Finnish European subpopulation (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). Use of the Bayesian point system for this variant with conflicting evidence. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121988/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:6 B:4
• Conservation: PhyloP100: 1.50
• Publications: 9 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

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.2131C>G	p.Leu711Val	missense_variant	Exon 13 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1948C>G	p.Leu650Val	missense_variant	Exon 12 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.583C>G	p.Leu195Val	missense_variant	Exon 13 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.166C>G	p.Leu56Val	missense_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.2131C>G	p.Leu711Val	missense_variant	Exon 13 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250252 AF XY: 0.00000739

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461066 Hom.: 0 Cov.: 34 AF XY: 0.0000316 AC XY: 23 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:6 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:2 Benign:1

Jul 11, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 07, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Sep 01, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP6, PM2_supporting -

Apr 25, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with gastric cancer as well as in healthy controls (PMID: 28352678); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8075649, 9744472, 15235021, 28352678) -

Hereditary cancer-predisposing syndrome Benign:2

Feb 16, 2021

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. -

Jul 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Endometrial carcinoma Pathogenic:1

May 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Apr 18, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 p.Leu711Val variant was identified in the heterozygous or homozygous state in 41 of 359 Chinese probands with gastric cancer and in 25 of 368 healthy individuals, although the allele frequencies could not be calculated for either population as the frequencies of heterozygotes and homozygotes were not provided separately (Lin 2014). This variant has also been reported somatically in an endometrial carcinoma with no evidence of loss of heterozygosity in tumour tissue (Risinger 1994). The variant was identified in dbSNP (ID: rs121964871) as “With Pathogenic allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color and Counsyl). The variant was identified in control databases in 2 of 276082 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 126488 chromosomes (freq: 0.000016), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu711 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

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

Aug 18, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.2131C>G variant is <1/50,000 alleles (0.002%, 2/128,916 alleles) in the non-Finnish European subpopulation (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). Use of the Bayesian point system for this variant with conflicting evidence. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.86	D;D;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.025
Sift	Benign	0.34	T;.;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.86	P;.;.
Vest4		0.19
MutPred		0.41		Gain of helix (P = 0.132);.;.;
MVP		0.77
MPC		0.50
ClinPred		0.40	T
GERP RS		3.1
Varity_R		0.068
gMVP		0.56
Mutation Taster		=88/12	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: rs121964871; hg19: chr16-68857496; COSMIC: COSV55745751; COSMIC: COSV55745751;