chr16-68808535-G-A

Variant names:

• chr16-68808535-G-A
• rs769076258
• NM_004360.5:c.499G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.499G>A (p.Glu167Lys) variant has also been observed in >10 (28) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000329225.7; SCV000259296.7). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA350337/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:7
• Conservation: PhyloP100: 0.344
• 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: Likely_benign. The variant received -4 ACMG points.

• 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.499G>A	p.Glu167Lys	missense_variant	Exon 4 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.499G>A	p.Glu167Lys	missense_variant	Exon 4 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1117G>A		5_prime_UTR_variant	Exon 4 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1321G>A		5_prime_UTR_variant	Exon 4 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.499G>A	p.Glu167Lys	missense_variant	Exon 4 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251348 AF XY: 0.0000147

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:2 Benign:3

Jul 31, 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 03, 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. -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS2 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Feb 15, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 167 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 4/282610 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jul 10, 2024

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. -

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2024

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.499G>A (p.Glu167Lys) results in a conservative amino acid change located in the cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 1614014 control chromosomes, predominantly at a frequency of 2.5e-05 within the Non-Finnish European subpopulation in the gnomAD database (v4). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer phenotype (2.1e-05). c.499G>A has been reported in the literature in an individual affected with breast cancer without evidence for causality (Tung_2016) and in an individual affected with colorectal cancer (Pearlman_2021) who had a co-occurring pathogenic variant (MUTYH c.536A>G, p.Tyr179Cys), providing supporting evidence for a benign role. These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26976419, 34250417). ClinVar contains an entry for this variant (Variation ID: 219431). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial cancer of breast;C0476089:Endometrial carcinoma;C1140680:Ovarian cancer;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Uncertain:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of breast cancer and in an individual with mismatch repair (MMR) proficient colorectal cancer (Tung et al., 2016; Pearlman et al., 2021; Garcia-Pelaez et a., 2023); This variant is associated with the following publications: (PMID: 36436516, 22850631, 15235021, 34250417, 26976419) -

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

Aug 10, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.499G>A (p.Glu167Lys) variant has also been observed in >10 (28) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000329225.7; SCV000259296.7). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;T;T;.;.
Eigen	Benign	0.091
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.85	T;T;T;T;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M;.;.;.;M
PhyloP100		0.34
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;.;.;.;N
REVEL	Benign	0.15
Sift	Benign	0.091	T;.;.;.;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.95	P;.;.;.;.
Vest4		0.41
MutPred		0.49		Gain of methylation at E167 (P = 0.0097);Gain of methylation at E167 (P = 0.0097);Gain of methylation at E167 (P = 0.0097);Gain of methylation at E167 (P = 0.0097);Gain of methylation at E167 (P = 0.0097);
MVP		0.76
MPC		0.87
ClinPred		0.54	D
GERP RS		2.8
Varity_R		0.28
gMVP		0.56
Mutation Taster		=86/14	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: rs769076258; hg19: chr16-68842438;