rs864622655

Positions:

• chr16-68808535-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5_Supporting PVS1 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.504delA p.(Gly169Alafs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; DOI: 10.1200/PO.16.00021). In summary, 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA348941/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 2.51

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.504delA	p.Gly169fs	frameshift_variant	4/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.504delA	p.Gly169fs	frameshift_variant	4/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1112delA		5_prime_UTR_variant	4/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1316delA		5_prime_UTR_variant	4/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.504delA	p.Gly169fs	frameshift_variant	4/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 02-23-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 09, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change creates a premature translational stop signal (p.Gly169Alafs*46) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 220776). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

Mar 18, 2024

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 01, 2024

Variant summary: CDH1 c.504delA (p.Gly169AlafsX46) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251348 control chromosomes. c.504delA has been reported in the literature in individual(s) affected with Breast Cancer (e.g. Adib_2022). The following publication have been ascertained in the context of this evaluation (PMID: 34949788). ClinVar contains an entry for this variant (Variation ID: 220776). Based on the evidence outlined above, the variant was 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 25, 2023

The c.504delA p.(Gly169Alafs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; DOI: 10.1200/PO.16.00021). In summary, 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.504delA pathogenic mutation, located in coding exon 4 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 504, causing a translational frameshift with a predicted alternate stop codon (p.G169Afs*46). This alteration has been reported in a family meeting International Gastric Cancer Linkage Consortium (IGCLC) guidelines for hereditary diffuse gastric cancer (HDGC) (Lowstuter K et al. JCO Precision Oncology, 2017 Mar;1,1-12). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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: rs864622655; hg19: chr16-68842438;