rs35187787

chr16-68822063-G-Achr16-68822063-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004360.5(CDH1):c.1774G>A(p.Ala592Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,614,062 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A592D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0051 (26 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel B:30 O:1
• Conservation: PhyloP100: 9.20

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018004835).
• BP6: Variant 16-68822063-G-A is Benign according to our data. Variant chr16-68822063-G-A is described in ClinVar as [Benign]. Clinvar id is 41783.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68822063-G-A is described in Lovd as [Likely_benign]. Variant chr16-68822063-G-A is described in Lovd as [Benign]. Variant chr16-68822063-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00311 (473/152206) while in subpopulation NFE AF= 0.00522 (355/68020). AF 95% confidence interval is 0.00477. There are 2 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 474 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1774G>A	p.Ala592Thr	missense_variant	12/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1591G>A	p.Ala531Thr	missense_variant	11/15
CDH1	NM_001317185.2	c.226G>A	p.Ala76Thr	missense_variant	12/16
CDH1	NM_001317186.2	c.-192G>A		5_prime_UTR_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1774G>A	p.Ala592Thr	missense_variant	12/16	1	NM_004360.5	P1
	ENST00000563916.1	n.263+1201C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 474 AN: 152088 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00325 AC: 818 AN: 251486 Hom.: 5 AF XY: 0.00328 AC XY: 446 AN XY: 135916

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00333

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00472

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00514 AC: 7507 AN: 1461856 Hom.: 26 Cov.: 32 AF XY: 0.00508 AC XY: 3697 AN XY: 727228

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00407

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.00590

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152206 Hom.: 2 Cov.: 31 AF XY: 0.00304 AC XY: 226 AN XY: 74408

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00454 Hom.: 1

Bravo AF: 0.00297

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00321 AC: 390

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00474

ClinVar

Significance: Benign

Submissions summary: Benign:30 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:9

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CDH1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 26, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:6 Other:1

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH1 p.Ala592Thr variant was identified in 19 of 5458 proband chromosomes (frequency: 0.003) from individuals or families with gastric, breast and ovarian cancers; and was present in 8 of 1472 control chromosomes (frequency: 0.005) from healthy individuals (Garziera 2013, Huiping 2001, Salahshor 2001, Schrader 2011, Stuebs 2017, Valente 2014). The variant was also identified in dbSNP (ID: rs35187787) as “with Uncertain significance, other allele”. In addition, the variant was identified in the ClinVar and Clinvitae database (as likely benign by GeneDx, Illumina clinical Services, Centre for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Pathway Genomics, CSER, University of Washington; as benign by Invitae, Ambry Genetics, Vantari Genetics; and with uncertain significance by Biesecker Lab/Human Development Section, NIH). The variant was also listed in the Cosmic database 4x as pathogenic with a FATHMM prediction score of 0.99; in the Insight Colon Cancer Gene Variant Database 6x (frequency 0.003), and in the Zhejiang Colon Cancer Database 3x. The variant was not identified in the MutDB database. Furthermore, the variant was also listed in the 1000 Genomes Project in 6 of 5000 chromosomes (frequency: 0.001) and in the NHLBI GO Exome Sequencing Project in 54 of 8600 European American alleles and in 5 of 4396 African American alleles. The variant was identified in control databases in 893 of 277218 chromosomes (4 homozygous) at a frequency of 0.003 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 21 of 24028 chromosomes (freq: 0.0009), Other in 24 of 6464 chromosomes (freq: 0.004), Latino in 65 of 34420 chromosomes (freq: 0.002), European Non-Finnish in 609 of 126710 chromosomes (freq: 0.005), Ashkenazi Jewish in 30 of 10152 chromosomes (freq: 0.003), Finnish in 43 of 25794 chromosomes (freq: 0.002), and South Asian in 101 of 30782 chromosomes (freq: 0.003); while the variant was not observed in the East Asian population. In one study, the frequency (0.06, n=3) of the p.Ala592Thr variant in 50 gastric tumors is almost four-fold that in normal population, suggesting that this variant indeed contributed to the tumorigenesis in a subset of gastric tumors. The authors concluded that the p.Ala592Thr variant may increase the lifetime risk of developing gastric cancer as a low penetrance variant (Huiping 2001). However allelic association studies do not support an effect of this alteration in predisposing to breast cancer in general as the variant was seen at similar frequencies between case and control groups (Salahshor 2001). In further research the p.Ala592Thr variant was again identified in both cases and controls, suggesting an improbable effect on gastric cancer pathogenesis. (Garziera 2013). In addition functional studies also support a non-pathogenic role; the p.Ala592Thr variant shows no detectable effect on adhesion activation and behaves like wild-type E-cadherin when treated with adhesion activating reagents (Petrova 2016), and cells expressing the E-cadherin variant behave like wild-type in regards to migration and aggregation (Kreller 2004). The p.Ala592 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and 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 this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary diffuse gastric adenocarcinoma Benign:5

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2020	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 17, 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. -

CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:2

Benign, reviewed by expert panel	curation	ClinGen CDH1 Variant Curation Expert Panel	Aug 08, 2023	The c.1774G>A (p.Ala592Thr) variant has an allele frequency of 0.00481 (0.48%, 609/126,710 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). 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. -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Oct 03, 2023	BA1 based on allele frequency in NFE of 0.00472 in gnomAD. -

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 10, 2022

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

Breast neoplasm Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;T;T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T;D;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.
MutationTaster	Benign	0.68	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D;.;.;.;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;.;.;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.49	P;.;.;.;.
Vest4		0.20
MVP		0.86
MPC		0.29
ClinPred		0.043	T
GERP RS		5.6
Varity_R		0.20
gMVP		0.58

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: rs35187787; hg19: chr16-68855966; COSMIC: COSV55738864; COSMIC: COSV55738864;