chr16-68738318-G-T

Variant names:

• chr16-68738318-G-T
• rs121964876
• NM_004360.5:c.70G>T

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.70G>T	p.Glu24*	stop_gained	Exon 2 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.70G>T	p.Glu24*	stop_gained	Exon 2 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1546G>T		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1750G>T		5_prime_UTR_variant	Exon 2 of 15		NP_001304115.1

Ensembl

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

Jan 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. ClinVar contains an entry for this variant (Variation ID: 12240). For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Aug 29, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Apr 19, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.3
Vest4		0.91
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121964876; hg19: chr16-68772221; COSMIC: COSV55730999;