rs587783048

Positions:

• chr16-68829752-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4 PVS1_Strong PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2398delC (p.Arg800Alafs*16) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 17545690). This variant was also found to co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; PMID:17545690). 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_Strong, PM2_Supporting, PS4, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA281459/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.92

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 10 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.
• PP1: 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.2398delC	p.Arg800fs	frameshift_variant	15/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2215delC	p.Arg739fs	frameshift_variant	14/15		NP_001304113.1
CDH1	NM_001317185.2	c.850delC	p.Arg284fs	frameshift_variant	15/16		NP_001304114.1
CDH1	NM_001317186.2	c.433delC	p.Arg145fs	frameshift_variant	14/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2398delC	p.Arg800fs	frameshift_variant	15/16	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 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 15, 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	Aug 08, 2022	ClinVar contains an entry for this variant (Variation ID: 156497). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CDH1 protein in which other variant(s) (p.Phe810Leufs*6) have been determined to be pathogenic (PMID: 26182300; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant is also known as a founder mutation that segregated with DGC and LBC in multiple families originating from Newfoundland (PMID: 17545690). This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer (DGC) and lobular breast cancer (LBC) (PMID: 17545690, 23709761, 24366306). It is commonly reported in individuals of Newfoundland ancestry (PMID: 17545690, 23709761, 24366306). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg800Alafs*16) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the CDH1 protein. -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2024	Frameshift variant in the C-terminus predicted to result in protein truncation as the last 82 amino acids are lost and replaced with 15 incorrect amino acids (HGMD); Observed in individuals with hereditary diffuse gastric cancer and invasive lobular breast cancer (PMID: 24366306, 34949788, 23709761, 19269290, 17545690); Co-segregated with hereditary diffuse gastric cancer and lobular breast cancer in multiple families and report as a founder variant in Newfoundland (PMID: 17545690); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24366306, 26759166, 18161866, 19408054, 17545690, 23709761, 18427545, 18007144, 19269290, 22225527, 20373070, 21696387, 18046629, 27752808, 30311375, 29798843, 30745422, 15235021, 22850631, 34949788) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

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

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 29, 2023

The c.2398delC (p.Arg800Alafs*16) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 17545690). This variant was also found to co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; PMID: 17545690). 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_Strong, PM2_Supporting, PS4, PP1. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2024

The c.2398delC pathogenic mutation, located in coding exon 15 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 2398, causing a translational frameshift with a predicted alternate stop codon (p.R800Afs*16). This alteration occurs at the 3' terminus of the CDH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 9% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation was reported in four HDGC families from the southeast coast of Newfoundland who shared a common haplotype, suggesting a founder effect. Based on clinical data obtained from the families, the authors were able to estimate the penetrance of the c.2398delC mutation. The cumulative risk of gastric cancer by age 75 for these four families was estimated to be 40% (95% CI 12%-91%) for males and 63% (95% CI 19%-99%) for females, and a cumulative risk for female breast cancer by age 75 was estimated to be 52% (95% CI 29%-94%) (Kaurah P et al. JAMA, 2007 Jun;297:2360-72). This alteration was also identified in a patient diagnosed with bilateral LCIS and unilateral ILC in her 30's (Petridis C et al. Br. J. Cancer, 2014 Feb;110:1053-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant 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: rs587783048; hg19: chr16-68863655;