16-68833439-C-T

Position:

• chr16-68833439-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_004360.5(CDH1):​c.2589C>T​(p.Asn863Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -2.83

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-68833439-C-T is Benign according to our data. Variant chr16-68833439-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136067.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=5}. Variant chr16-68833439-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.83 with no splicing effect.
• BS2: High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2589C>T	p.Asn863Asn	synonymous_variant	16/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2406C>T	p.Asn802Asn	synonymous_variant	15/15		NP_001304113.1
CDH1	NM_001317185.2	c.1041C>T	p.Asn347Asn	synonymous_variant	16/16		NP_001304114.1
CDH1	NM_001317186.2	c.624C>T	p.Asn208Asn	synonymous_variant	15/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2589C>T	p.Asn863Asn	synonymous_variant	16/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251476 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135912

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000340 AC: 497 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000331 AC XY: 241 AN XY: 727242

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000417

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74452

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000264

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1 Benign:4

Uncertain significance, 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	BP7 (PMID: 30311375) -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 06, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2016	Variant summary: The c.2589C>T (p.Asn863=) in CDH1 gene is a synonymous change that involves a non-conserved nucleotide. The variant is present in the control population dataset of ExAC at frequency of 0.00016 (19/121410 chrs tested). This frequency exceeds the maximal expected frequency of a pathogenic allele (0.000028) in this gene. The variant of interest was cited as Likely Benign/Benign by reputable database/clinical laboratories. Taking together, the variant was classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CDH1: BP4, BP7 -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 14, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 15, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 02, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

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

Sep 03, 2021

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CDH1 p.Asn863= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs115817750) as With Likely benign, Uncertain significance allele, ClinVar (classified as likely benign by Invitae, Ambry Genetics, Counsyl, Color Genomics; classified as benign by GeneDx, IGLCA). The variant was identified in control databases in 49 of 277226 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 8 of 24032 chromosomes (freq: 0.0003), European in 37 of 126712 chromosomes (freq: 0.0003), East Asian in 4 of 18870 chromosomes (freq: 0.0002); it was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Asn863= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.6
DANN	Benign	0.73

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: rs115817750; hg19: chr16-68867342;