rs1555509636

Positions:

• chr16-68737427-G-A
• chr16-68737427-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5_Supporting PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.12G>A (p.Trp4Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396451249/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH1 NM_004360.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: -0.0380

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.12G>A	p.Trp4*	stop_gained	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.12G>A	p.Trp4*	stop_gained	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1604G>A		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1808G>A		5_prime_UTR_variant	1/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.12G>A	p.Trp4*	stop_gained	1/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.12G>A	p.Trp4*	stop_gained	1/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.12G>A		non_coding_transcript_exon_variant	1/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.12G>A		non_coding_transcript_exon_variant	1/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 27, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 20, 2020	The p.W4* variant (also known as c.12G>A), located in coding exon 1 of the CDH1 gene, results from a G to A substitution at nucleotide position 12. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration was identified in an individual at risk for hereditary cancer referred for multigene panel testing (Schroeder C et al. Breast Cancer Res. Treat. 2015 Jul;152(1):129-136). The predicted stop codon for this alteration occurs within the first 150 nucleotides of the CDH1 gene. Therefore, this alteration may escape nonsense-mediated mRNA decay and/or be rescued by reinitiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). However, the impacted region is critical for protein function (van Roy F et al. Cell. Mol. Life Sci. 2008 Nov;65(23):3756-88; Shapiro L et al. Cold Spring Harb Perspect Biol 2009 Sep;1(3):a003053; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This variant changes 1 nucleotide in exon 1 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to disrupt the signal sequence of the protein and result in an absent or non-functional protein product. To our knowledge, this variant has been reported in an individual with a high-risk family profile indicative for hereditary breast and ovarian cancer (PMID: 26022348). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

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

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 04, 2023

The c.12G>A (p.Trp4Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Benign	0.94
Eigen	Benign	0.0071
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.016	N
Vest4		0.59
GERP RS		-1.0

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: rs1555509636; hg19: chr16-68771330; COSMIC: COSV55729433;