rs34033771

chr16-68737345-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004360.5(CDH1):c.-71C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,328,408 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (8 hom., cov: 33)
  • Exomes 𝑓: 0.012 (99 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: -0.210

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=-0.68).
• BP6: Variant 16-68737345-C-G is Benign according to our data. Variant chr16-68737345-C-G is described in ClinVar as [Benign]. Clinvar id is 221174.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00922 (1405/152322) while in subpopulation NFE AF= 0.0137 (934/68008). AF 95% confidence interval is 0.013. There are 8 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1404 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.-71C>G		5_prime_UTR_variant	1/16	ENST00000261769.10
CDH1	NM_001317184.2	c.-71C>G		5_prime_UTR_variant	1/15
CDH1	NM_001317185.2	c.-1686C>G		5_prime_UTR_variant	1/16
CDH1	NM_001317186.2	c.-1890C>G		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.-71C>G		5_prime_UTR_variant	1/16	1	NM_004360.5	P1
CDH1	ENST00000566612.5	c.-71C>G		5_prime_UTR_variant, NMD_transcript_variant	1/15	1
CDH1	ENST00000422392.6			upstream_gene_variant		1
CDH1	ENST00000566510.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1404 AN: 152212 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.0119 AC: 14031 AN: 1176086 Hom.: 99 Cov.: 16 AF XY: 0.0117 AC XY: 6878 AN XY: 588062

Gnomad4 AFR exome AF: 0.00139

Gnomad4 AMR exome AF: 0.00661

Gnomad4 ASJ exome AF: 0.00427

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00582

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.00978

GnomAD4 genome AF: 0.00922 AC: 1405 AN: 152322 Hom.: 8 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74488

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.0133 Hom.: 2

Bravo AF: 0.00751

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CDH1: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	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. -

Hereditary diffuse gastric adenocarcinoma Benign:4

Benign, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	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	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; BP2_Supporting (PMID: 30311375) -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Neoplasm of ovary;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

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.-71C>G variant has an allele frequency of 0.01628 (1.628%, 251/15418 alleles, 2 homozygotes) in the European (Non-Finnish) 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. -

Malignant tumor of prostate Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

May 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	11
Dann	Benign	0.79

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: rs34033771; hg19: chr16-68771248;