16-68819394-G-C

Position:

• chr16-68819394-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004360.5(CDH1):​c.1680G>C​(p.Thr560=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,613,740 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (26 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: -3.61

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-68819394-G-C is Benign according to our data. Variant chr16-68819394-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 136697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68819394-G-C is described in Lovd as [Likely_benign]. Variant chr16-68819394-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00261 (398/152234) while in subpopulation SAS AF= 0.00519 (25/4816). AF 95% confidence interval is 0.00361. There are 0 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1680G>C	p.Thr560=	synonymous_variant	11/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1497G>C	p.Thr499=	synonymous_variant	10/15		NP_001304113.1
CDH1	NM_001317185.2	c.132G>C	p.Thr44=	synonymous_variant	11/16		NP_001304114.1
CDH1	NM_001317186.2	c.-254-2607G>C		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1680G>C	p.Thr560=	synonymous_variant	11/16	1	NM_004360.5	ENSP00000261769	P1
	ENST00000563916.1	n.264-3735C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00337 AC: 848 AN: 251482 Hom.: 4 AF XY: 0.00386 AC XY: 524 AN XY: 135914

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00686

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00352 AC: 5151 AN: 1461506 Hom.: 26 Cov.: 32 AF XY: 0.00366 AC XY: 2662 AN XY: 727044

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00698

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00373

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74422

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00272 Hom.: 0

Bravo AF: 0.00223

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:9

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH1 p.Thr560= variant was identified in the literature in 1 of 20 normal chromosomes (frequency: 0.025); however the frequency of this variant in an affected population was not provided (Berx 1997). The variant was also identified in dbSNP (ID: rs35741240) as “With Likely benign, other allele”, in the ClinVar database as benign by GeneDx, Ambry Genetics, EGL Genetic Diagnostics, Invitae, ARUP Laboratories and as likely benign by Illumina Clinical Services; in the Clinvitae database as benign by EmyClass; and in the Cosmic and in Zhejiang Colon Cancer Databases 1X in haemangioblastoma. The variant was not identified in MutDB or the Insight Colon Cancer Gene Variant databases. The variant was further identified in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002) and in the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and 3 in 4396 in African American alleles. The variant was identified in control databases in 925 of 277220 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). Breakdown of the observations by population include African in 19 of 24022 chromosomes (freq: 0.0008), other in 14 of 6464 chromosomes (freq: 0.002), Latino in 46 of 34420 chromosomes (freq: 0.001), European Non-Finnish in 573 of 126722 chromosomes (freq: 0.004), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), East Asian in 2 of 18868 chromosomes (freq: 0.0001), European Finnish in 52 of 25794 chromosomes (freq: 0.002), and South Asian in 211 of 30778 chromosomes (freq: 0.007). The p.Thr560= 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CDH1: BP4, BP7, BS2 -

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 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)	Jun 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely 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	Genetic Services Laboratory, University of Chicago	Jan 06, 2021	- -

Hereditary diffuse gastric adenocarcinoma Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Jan 04, 2018	CDH1 p.T560T (NM_004360.3:c.1680G>C) has been reported at a frequency of approximately 1 in 100 individuals of European ancestry (exac.broadinstitute.org). This variant frequency is too high to be consistent with the cancer risk syndrome seen with pathogenic CDH1 variants (Hansford 2015). This evidence supports classification of this variant as likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. -
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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 26, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 15, 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. -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 12, 2023

- -

Malignant tumor of prostate Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0040
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35741240; hg19: chr16-68853297; COSMIC: COSV55731541; COSMIC: COSV55731541;