16-68738318-G-T

Position:

• chr16-68738318-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5_Supporting PVS1 PP1 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.70G>T p.(Glu24Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID:10477433, 11104024). The variant was also found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; PMID:10477433, 11104024). 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, PP1, PS4_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280997/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 2.28

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 12 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.
• 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.70G>T	p.Glu24*	stop_gained	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.70G>T	p.Glu24*	stop_gained	2/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1546G>T		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1750G>T		5_prime_UTR_variant	2/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.70G>T	p.Glu24*	stop_gained	2/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.70G>T	p.Glu24*	stop_gained	2/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.70G>T		non_coding_transcript_exon_variant	2/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.70G>T		non_coding_transcript_exon_variant	2/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2023	This sequence change creates a premature translational stop signal (p.Glu24*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12240). This premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (HDGC) (PMID: 10477433). It has also been observed to segregate with disease in related individuals. -

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.70G>T p.(Glu24Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 10477433, 11104024). The variant was also found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; PMID: 10477433, 11104024). 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, PP1, PS4_Supporting, PM5_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2022

The p.E24* pathogenic mutation (also known as c.70G>T), located in coding exon 2 of the CDH1 gene, results from a G to T substitution at nucleotide position 70. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This mutation has been detected in two families with strong histories of diffuse gastric cancer as well as in an individual with signet ring cell carcinoma (Guilford PJ et al. Hum. Mutat., 1999;14:249-55; Lynch HT et al. Cancer, 2008 Jun;112:2655-63; Lee HE et al. Hum. Pathol., 2018 Jan;:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Benign	0.74	D
Vest4		0.91
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121964876; hg19: chr16-68772221; COSMIC: COSV55730999; COSMIC: COSV55730999;