rs139866691

Positions:

• chr16-68738336-C-A
• chr16-68738336-C-G
• chr16-68738336-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The c.88C>A (p.Pro30Thr) variant has an allele frequency of 0.00249 (0.25%, 178/71372 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In addition to meeting stand along criteria for a benign classification, this variant has also been seen in >900 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). In summary, 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, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA151524/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:24 O:1
• Conservation: PhyloP100: 0.584

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 -12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.88C>A	p.Pro30Thr	missense_variant	2/16	ENST00000261769.10
CDH1	NM_001317184.2	c.88C>A	p.Pro30Thr	missense_variant	2/15
CDH1	NM_001317185.2	c.-1528C>A		5_prime_UTR_variant	2/16
CDH1	NM_001317186.2	c.-1732C>A		5_prime_UTR_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.88C>A	p.Pro30Thr	missense_variant	2/16	1	NM_004360.5	P1
CDH1	ENST00000422392.6	c.88C>A	p.Pro30Thr	missense_variant	2/15	1
CDH1	ENST00000566612.5	c.88C>A	p.Pro30Thr	missense_variant, NMD_transcript_variant	2/15	1
CDH1	ENST00000566510.5	c.88C>A	p.Pro30Thr	missense_variant, NMD_transcript_variant	2/15	5

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 174 AN: 140546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000706

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000677

Gnomad FIN AF: 0.000396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00134 AC: 210 AN: 156216 Hom.: 0 AF XY: 0.00125 AC XY: 103 AN XY: 82324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000266

Gnomad FIN exome AF: 0.000122

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00214 AC: 2984 AN: 1391182 Hom.: 3 Cov.: 31 AF XY: 0.00206 AC XY: 1413 AN XY: 686074

Gnomad4 AFR exome AF: 0.000159

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.000388

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00168

GnomAD4 genome AF: 0.00124 AC: 174 AN: 140664 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 83 AN XY: 68820

Gnomad4 AFR AF: 0.000343

Gnomad4 AMR AF: 0.000705

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000678

Gnomad4 FIN AF: 0.000396

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00121

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00161 AC: 11

ExAC AF: 0.000561 AC: 21

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:24 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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	BA1; BS2 (PMID: 30311375) -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 27, 2016	- -

not specified Uncertain:1 Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2020	Variant summary: CDH1 c.88C>A (p.Pro30Thr) results in a non-conservative amino acid change located in the Cadherin prodomain (IPR014868) 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 0.0013 in 156216 control chromosomes. The observed variant frequency is approximately 47 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. c.88C>A has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MUTYH c.1227_1228dupGG, p.Glu410Glyfs*43; CTNNA1 c.76delGA, p.Arg27ThrfsX17; CHEK2 c.1100delC, p.T367fs*15), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating reduced localization of the variant protein to the plasma membrane, slightly decreased cell aggregation and minor increase in the invasion capacity of cells expressing the variant however, these results do not allow convincing conclusions about the variant effect (Vogelaar 2012). Thirteen clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (12x benign/likely benign, 1x VUS, expert panel benign). Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Detected in 2 patients with orofacial clefts (Vogelaar 2013). Gene is strongly asociated with gastric cancer, there is limited evidence for association with orofacial clefts. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 05, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH1 p.Pro30Thr variant was identified in 5 of 3312 proband chromosomes (frequency: 0.0015) from individuals or families with lobular breast cancer and Lynch syndrome and was present in 11 of 17412 control chromosomes (frequency: 0.0006) from healthy individuals (Molinaro 2014, Sarrio 2003, Schrader 2011, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs139866691) as “With other allele”, ClinVar (as benign by Invitae and Ambry Gentics, likely benign by GeneDx, Illumina, Counsyl, Color Genomics, Laboratory for Molecular Medicine, University of Chicago, and University of Washington Medical Center, and as uncertain significance by Knight Diagnostic Laboratories), Clinvitae (4x with conflicting interpretations of pathogenicity), Cosmic (seen in breast cancer), Insight Colon Cancer Gene Variant Database (2x), and Zhejiang Colon Cancer Database (2x). The variant was not identified in the MutDB database. The variant was identified in control databases in 232 of 178576 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 15728 chromosomes (freq: 0.0002), Other in 11 of 4718 chromosomes (freq: 0.002), Latino in 31 of 24390 chromosomes (freq: 0.001), European in 178 of 71372 chromosomes (freq: 0.002), Finnish in 3 of 19552 chromosomes (freq: 0.0002), and South Asian in 6 of 22566 chromosomes (freq: 0.0003), while the variant was not observed in the Ashkenazi Jewish or East Asian populations. In a functional study in which RT-PCR was performed, the protein transcript was found to be normal (Molinaro 2014). A study of CDH1 variants in Hereditary Diffuse Gastric Cancer (HDGC) patients using in silico tools concluded the variant was structurally tolerated (Simoes Correia 2012). The variant was also found in 2 patients with orofacial clefts; during embryonic development, the cell adhesion molecule E-cadherin, encoded by CDH1, is highly expressed in the median edge epithelium of the palate (Vogelaar 2013). The p.Pro30 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, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25593300, 29958926, 26483394, 29348693, 29589180, 26022348, 27616075, 28944238, 27978560, 25637381, 28135145, 15831593, 10094558, 27443514, 27153395, 26759166, 27146957, 26976419, 26123647, 26072394, 25980754, 12800196, 20921021, 24493355, 23197654, 22470475, 24728327, none) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CDH1: BS1 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 31, 2017	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 27, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jul 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 07, 2014	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2020	- -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

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

Jan 18, 2023

- -

Orofacial cleft Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.88C>A (p.Pro30Thr) variant has an allele frequency of 0.00249 (0.25%, 178/71372 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In addition to meeting stand along criteria for a benign classification, this variant has also been seen in >900 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). In summary, 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, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D;.;.;.;D
REVEL	Uncertain	0.59
Sift	Benign	0.36	T;.;.;.;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.99	D;.;.;.;.
Vest4		0.59
MVP		0.96
MPC		0.40
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.17
gMVP		0.75

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: rs139866691; hg19: chr16-68772239; COSMIC: COSV104558612; COSMIC: COSV104558612;