16-68834619-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004360.5(CDH1):c.*1120T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 241,904 control chromosomes in the GnomAD database, including 3,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2356 hom., cov: 32)
  • Exomes 𝑓: 0.17 (1398 hom.)
• Consequence: CDH1 NM_004360.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.682

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-68834619-T-C is Benign according to our data. Variant chr16-68834619-T-C is described in ClinVar as [Benign]. Clinvar id is 320291.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.*1120T>C		3_prime_UTR_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.*1120T>C		3_prime_UTR_variant	15/15
CDH1	NM_001317185.2	c.*1120T>C		3_prime_UTR_variant	16/16
CDH1	NM_001317186.2	c.*1120T>C		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.*1120T>C		3_prime_UTR_variant	16/16	1	NM_004360.5	P1
CDH1	ENST00000566612.5	c.*2009T>C		3_prime_UTR_variant, NMD_transcript_variant	15/15	1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27019 AN: 152114 Hom.: 2351 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.170 AC: 15218 AN: 89672 Hom.: 1398 Cov.: 0 AF XY: 0.168 AC XY: 7101 AN XY: 42196

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.0896

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.178 AC: 27063 AN: 152232 Hom.: 2356 Cov.: 32 AF XY: 0.177 AC XY: 13165 AN XY: 74444

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.194

Gnomad4 OTH AF: 0.167

Alfa AF: 0.186 Hom.: 1086

Bravo AF: 0.179

Asia WGS AF: 0.150 AC: 519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:1

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. -

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 10, 2023

The NM_004360.5(CDH1):c.*1120T>C variant has an allele frequency of 0.21013 (21%, 730/3474 alleles, 79 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, 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, BP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.36
Dann	Benign	0.52

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: rs13689; hg19: chr16-68868522; COSMIC: COSV55740499; COSMIC: COSV55740499;