16-68737366-C-T

Position:

chr16-68737366-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.-50C>T variant occurs in the 5'UTR. This variant has an allele frequency of 0.00001 (1 in 151,862) in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome version GRCh37/hg19. To our knowledge, the c.-50C>T variant has not been reported in the literature. Other single nucleotide variants in the CDH1 promoter have been shown to alter promoter activity, the c.-49G>T variant slightly increasing activity and the c.-54G>C variant decreasing activity based on luciferase assays (PMID:23431106, 11996968). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16620222/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CDH1
NM_004360.5 5_prime_UTR

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 0.170

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
CDH1	NM_004360.5 linkuse as main transcript	c.-50C>T	5_prime_UTR_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.-50C>T	5_prime_UTR_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.-1665C>T	5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.-1869C>T	5_prime_UTR_variant	1/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.-50C>T	5_prime_UTR_variant	1/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1
CDH1	ENST00000422392.6 linkuse as main transcript	c.-50C>T	5_prime_UTR_variant	1/15	1		ENSP00000414946		P12830-2
CDH1	ENST00000566612.5 linkuse as main transcript	c.-50C>T	5_prime_UTR_variant, NMD_transcript_variant	1/15	1		ENSP00000454782
CDH1	ENST00000566510.5 linkuse as main transcript	c.-50C>T	5_prime_UTR_variant, NMD_transcript_variant	1/15	5		ENSP00000458139

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000148

AC:

AN:

1347364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

666006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000410

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.51e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2017

This variant is denoted CDH1 c.-50C>T, and describes a nucleotide substitution 50 base pairs upstream of the ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is GGCC[C/T]GACC. This variant does not appear to affect the start codon or the Kozak translational consensus sequence, and it is not predicted to affect splicing. The cytosine (C) nucleotide that is altered is not conserved across species. CDH1 c.-50C>T was not observed in large population cohorts; however, limited data are available (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Although this particular variant has not, to our knowledge, been published in the literature, variants have been reported in this region at c.-49 and c.-54 per HGMD (Stenson 2013). Luciferase reporter assays showed that c.-49G>T contributes to a slight increase in promoter activity, while c.-54G>C significantly decreases (p = 0.003) promoter activity (Nakamura 2002, Chen 2013). Based on currently available information, it is unclear whether CDH1 c.-50C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 21, 2023

The c.-50C>T variant occurs in the 5'UTR. This variant has an allele frequency of 0.00001 (1 in 151,862) in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome version GRCh37/hg19. To our knowledge, the c.-50C>T variant has not been reported in the literature. Other single nucleotide variants in the CDH1 promoter have been shown to alter promoter activity, the c.-49G>T variant slightly increasing activity and the c.-54G>C variant decreasing activity based on luciferase assays (PMID: 23431106, 11996968). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over