chr16-68737444-C-CGCT

Position:

chr16-68737444-C-CGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6_Very_StrongBS2_Supporting

The NM_004360.5(CDH1):c.44_46dupTGC(p.Leu15dup) variant causes a disruptive inframe insertion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000362 in 1,489,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CDH1
NM_004360.5 disruptive_inframe_insertion, splice_region

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel U:7B:4

Conservation

PhyloP100: -0.466

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 Benign. Variant got -9 ACMG points.

BP6

Variant 16-68737444-C-CGCT is Benign according to our data. Variant chr16-68737444-C-CGCT is described in ClinVar as [Likely_benign]. Clinvar id is 220798.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5 linkuse as main transcript	c.44_46dupTGC	p.Leu15dup	disruptive_inframe_insertion, splice_region_variant	1/16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.44_46dupTGC	p.Leu15dup	disruptive_inframe_insertion, splice_region_variant	1/16	1	NM_004360.5	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6 linkuse as main transcript	c.44_46dupTGC	p.Leu15dup	disruptive_inframe_insertion, splice_region_variant	1/15	1		ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5 linkuse as main transcript	n.44_46dupTGC		splice_region_variant, non_coding_transcript_exon_variant	1/15	1		ENSP00000454782.1	H3BNC6
CDH1	ENST00000566510.5 linkuse as main transcript	n.44_46dupTGC		splice_region_variant, non_coding_transcript_exon_variant	1/15	5		ENSP00000458139.1	H3BVI7

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

124448

Hom.:

AF XY:

0.0000146

AC XY:

AN XY:

68602

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000468

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000366

AC:

AN:

1337588

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

661354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000285

Gnomad4 SAS exome

AF:

0.0000773

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000394

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 08, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 10, 2016	- -
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	PM2 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	This variant causes a duplication of a leucine residue at codon 15 of the CDH1 protein, following 5 consecutive leucine residues. This variant is also known as 46insTGC in the literature. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary diffuse gastric cancer (PMID: 20373070), as well as in individuals and families whose phenotype is not consistent with hereditary diffuse gastric cancer (ClinVar SCV001437632.1; Color internal data). This variant has been identified in 1/124448 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2022	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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 1 amino acid in a repetitive region with no known function; Observed in a hereditary diffuse gastric cancer (HDGC) family as well as individuals with personal or family history of breast cancer (Guilford et al., 2010; Rodriguez-Balada et al., 2020; Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 15235021, 22225527, 20373070, 30068367, 31786208, 34855780, 36436516, 36243179, 32980694) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 26, 2023	In the published literature, this variant has been reported in affected families with hereditary diffuse gastric cancer (PMID: 20373070 (2010)), as well as in an affected individual with breast cancer (PMID: 31786208 (2020)). The frequency of this variant in the general population, 0.000008 (1/124448 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.32_34TGC[6] (p.Leu15dup), also referred to as 46insTGC, results in the in-frame insertion of a leucine residue in exon 1. This variant has been observed in more than 10 individuals with DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000566421.3, SCV000261647.7). This variant has also been reported in the literature in an HDGC family, but it is not known whether this family meets current IGCLC criteria (PMID: 20373070). In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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