16-68737423-C-G

Position:

• chr16-68737423-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.8C>G (p.Pro3Arg) variant has an allele frequency of 0.00025 (39/155276) in gnomAD and is observed in multiple subpopulations, with a maximum frequency of 0.00072 (7/9712) in the European (Finnish) subpopulation (http://gnomad.broadinstitute.org). This variant was observed more than 70 probands without a personal history of DGC, SRC tumours or LBC and whose families do not meet HDGC clinical criteria (BS2; SCV000210891.12, SCV000186617.6). The variant has also been identified in at least 5 individuals with LBC but whose families do not meet HDGC clinical criteria (PMID:20921021, SCV000210891.12). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. However, localization to the plasma membrane was not affected when the variant was expressed in cells lacking endogenous expression of E-cadherin (PMID:20921021). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. 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/CA294410/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:13 O:1
• Conservation: PhyloP100: 2.17

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 Likely_benign. Variant got -4 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.8C>G	p.Pro3Arg	missense_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.8C>G	p.Pro3Arg	missense_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1608C>G		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1812C>G		5_prime_UTR_variant	1/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.8C>G	p.Pro3Arg	missense_variant	1/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.8C>G	p.Pro3Arg	missense_variant	1/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.8C>G		non_coding_transcript_exon_variant	1/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.8C>G		non_coding_transcript_exon_variant	1/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152218 Hom.: 0 Cov.: 33

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: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000620 AC: 8 AN: 129088 Hom.: 0 AF XY: 0.0000704 AC XY: 5 AN XY: 71060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000633

Gnomad NFE exome AF: 0.0000417

Gnomad OTH exome AF: 0.000251

GnomAD4 exome AF: 0.000112 AC: 155 AN: 1381820 Hom.: 0 Cov.: 30 AF XY: 0.000116 AC XY: 79 AN XY: 682176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000850 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000441 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3 Benign:13 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 10, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	BS2 (PMID: 30311375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 06, 2023	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. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 06, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2019	This variant is associated with the following publications: (PMID: 27616075, 20921021, 25925381) -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2020	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 27, 2019	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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2022	Variant summary: CDH1 c.8C>G (p.Pro3Arg) results in a non-conservative amino acid change in 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 0.00024 in 160470 control chromosomes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. The variant, c.8C>G, has been reported in the literature in individuals affected with breast cancer, ovarian cancer or colorectal cancer (Schrader_2010, Kraus_2017, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=6, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Endometrial carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 17, 2018

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 08, 2022

- -

CDH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.8C>G (p.Pro3Arg) variant has an allele frequency of 0.00025 (39/155276) in gnomAD and is observed in multiple subpopulations, with a maximum frequency of 0.00072 (7/9712) in the European (Finnish) subpopulation (http://gnomad.broadinstitute.org). This variant was observed more than 70 probands without a personal history of DGC, SRC tumours or LBC and whose families do not meet HDGC clinical criteria (BS2; SCV000210891.12, SCV000186617.6). The variant has also been identified in at least 5 individuals with LBC but whose families do not meet HDGC clinical criteria (PMID: 20921021, SCV000210891.12). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. However, localization to the plasma membrane was not affected when the variant was expressed in cells lacking endogenous expression of E-cadherin (PMID: 20921021). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

Malignant tumor of breast;C1708349:Hereditary diffuse gastric adenocarcinoma Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Likely benign and reported on 11-18-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.65	T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.081	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;.;.;.;N
REVEL	Benign	0.085
Sift	Uncertain	0.0080	D;.;.;.;D
Sift4G	Uncertain	0.031	D;D;D;D;D
Polyphen		0.0010	B;.;.;.;.
Vest4		0.59
MutPred		0.47		Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);
MVP		0.78
MPC		0.92
ClinPred		0.11	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.058
gMVP		0.41

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: rs587782484; hg19: chr16-68771326; COSMIC: COSV99028645;