16-68737417-T-G

Variant names:

• chr16-68737417-T-G
• rs1555509623
• NM_004360.5:c.2T>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PS4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: The c.2T>G (p.Met1Arg) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in two probands/families meeting HDGC clinical criteria (PS4_Moderate; SCV000760846.2 and internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 2 as specified by the CDH1 Variant Curation Expert Panel (v3.1): PVS1, PM2_supporting, PS4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396451182/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH1 NM_004360.5 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 1.35

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2T>G	p.Met1?	start_lost	Exon 1 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2T>G	p.Met1?	start_lost	Exon 1 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1614T>G		5_prime_UTR_variant	Exon 1 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1818T>G		5_prime_UTR_variant	Exon 1 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2T>G	p.Met1?	start_lost	Exon 1 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.2T>G	p.Met1?	start_lost	Exon 1 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.2T>G		non_coding_transcript_exon_variant	Exon 1 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.2T>G		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:2

Jun 08, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. -

Nov 27, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CDH1 mRNA. The next in-frame methionine is located at codon 246. For these reasons, this variant has been classified as Pathogenic. Functional studies for this variant have not been reported. However, translation rescue by the downstream methionine at codon 246 would delete most of the first extracellular cadherin (EC1) domain (amino acid residues 155-262). This domain is important for the formation of intermolecular interactions with other CDH1 molecules to establish cell-cell junctions (PMID: 18726070, 2317870, 20066110). Several variants affecting the initiator methionine of the CDH1 mRNA (c.1A>G, c.2T>C, c.3G>C, c.3G>A) have been observed in individuals with a personal or family history of diffuse gastric cancer and/or lobular breast cancer (PMID: 28202063, 16061854, 20373070, Invitae). This suggests that variants that disrupt the initiator codon of the CDH1 protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 532474). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. -

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

Aug 25, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2T>G (p.Met1Arg) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in two probands/families meeting HDGC clinical criteria (PS4_Moderate; SCV000760846.2 and internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 2 as specified by the CDH1 Variant Curation Expert Panel (v3.1): PVS1, PM2_supporting, PS4_Moderate. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the loss of the translation start codon (methionine at codon 1) of the CDH1 gene. This variant is expected to disrupt the expression of the full-length CDH1 protein. While this particular nucleotide substitution has not been reported in literature, other variants (c.1A>G, c.2T>C, c.3G>C, c.3G>A) that result in the loss of p.Met1 have been observed in families affected with diffuse gastric cancer (PMID: 16061854, 20373070, 26182300) and lobular breast cancer (PMID: 28202063). 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. Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T;T;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Benign	-0.80	T
PROVEAN	Benign	-0.84	N;.;.;.;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.84	P;.;.;.;.
Vest4		0.77
MutPred		0.93		Gain of MoRF binding (P = 0.0244);Gain of MoRF binding (P = 0.0244);Gain of MoRF binding (P = 0.0244);Gain of MoRF binding (P = 0.0244);Gain of MoRF binding (P = 0.0244);
MVP		0.84
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.80

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: rs1555509623; hg19: chr16-68771320;