chr16-68822138-G-A

Position:

• chr16-68822138-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1,076/24,022 alleles) in the African 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121991/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (36 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel P:2 B:27 O:1
• Conservation: PhyloP100: 1.25

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 -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1849G>A	p.Ala617Thr	missense_variant	12/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1666G>A	p.Ala556Thr	missense_variant	11/15
CDH1	NM_001317185.2	c.301G>A	p.Ala101Thr	missense_variant	12/16
CDH1	NM_001317186.2	c.-117G>A		5_prime_UTR_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1849G>A	p.Ala617Thr	missense_variant	12/16	1	NM_004360.5	P1
	ENST00000563916.1	n.263+1126C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1969 AN: 152098 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00349 AC: 878 AN: 251466 Hom.: 18 AF XY: 0.00252 AC XY: 342 AN XY: 135904

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00143 AC: 2097 AN: 1461870 Hom.: 36 Cov.: 32 AF XY: 0.00127 AC XY: 924 AN XY: 727242

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 152216 Hom.: 49 Cov.: 31 AF XY: 0.0125 AC XY: 929 AN XY: 74412

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00230 Hom.: 15

Bravo AF: 0.0144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0471 AC: 207

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00422 AC: 513

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2 Benign:27 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary diffuse gastric adenocarcinoma Benign:6

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) -
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	Myriad Genetics, Inc.	Mar 07, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2016	- -

Hereditary cancer-predisposing syndrome Benign:6

Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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	clinical testing	Vantari Genetics	Jan 21, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 21, 2020	- -

not provided Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CDH1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -

DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 25, 2021

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 26, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CDH1 p.Ala617Thr variant was identified in 7 of 540 proband chromosomes (frequency: 0.013) from individuals or families with osteoblastic osteosarcoma, gastric adenocarcinoma, breast cancer and was present in 14 (all in African American) of 716 (516 African American) control chromosomes (frequency: 0.02) from healthy individuals (Choy 2012, El-Husny 2014, Suriano 2003, Valente 2014). The variant was also identified in dbSNP (ID: rs33935154) as With Pathogenic allele, ClinVar (classified as benign by GeneDx, Ambry Genetics, Pathway Genomics, Invitae, Vantari Genetics, Coulsyl; classified as pathogenic by OMIM), Clinvitae (conflicting interpretations of pathogenicity by ClinVar), Cosmic (neutral), databases. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 1211(25 homozygous) of 277184 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1076 of 24022 chromosomes (freq: 0.045). The p.Ala617 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. The variant is located with the Cadherin Cadherin-like functional domain increasing the liklihood that it may have clinical significance. Functional analysis by Suriano (2003) identified cells expressing the Ala617Thr mutation showed the same non-invasive behavior as cells expressing wild-type protein. The case study by Lajus (2015) found the variant in a family with no history of diffuse gastric cancer. The daughter diagnosed with in situ breast cancer does not carry the CDH1 mutation. The index case (72 year old) is alive without the evidence of breast or gastric cancer, and is on surveillance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 08, 2023

The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1,076/24,022 alleles) in the African 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.80	T;T;D;T
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.72	N;.;.;N
REVEL	Benign	0.087
Sift	Benign	0.51	T;.;.;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.040	B;.;.;.
Vest4		0.067
MVP		0.74
MPC		0.26
ClinPred		0.0033	T
GERP RS		3.5
Varity_R		0.037
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs33935154; hg19: chr16-68856041; COSMIC: COSV55727851; COSMIC: COSV55727851;