chr16-68737416-A-G

Variant names:

• chr16-68737416-A-G
• rs1555509622
• NM_004360.5:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4_Supporting PM2_Supporting PP1 PVS1

This summary comes from the ClinGen Evidence Repository: The c.1A>G (p.Met1Val) 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 at least one proband meeting HDGC clinical criteria (PS4_supporting; SCV000760810.2). This variant was also found to co-segregate with disease in multiple affected family members (PP1; SCV000760810.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PS4_supporting, PM2_supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396451176/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 1.85

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.
• 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.1A>G	p.Met1?	start_lost	Exon 1 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1A>G	p.Met1?	start_lost	Exon 1 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1615A>G		5_prime_UTR_variant	Exon 1 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1819A>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.1A>G	p.Met1?	start_lost	Exon 1 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.1A>G	p.Met1?	start_lost	Exon 1 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1381104 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 681762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

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. -

Feb 07, 2024

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. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with a personal or family history of diffuse gastric cancer and/or lobular breast cancer (PMID: 16061854, 20373070, 28202063; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 532457). For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 16, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the CDH1 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Though this exact mutation has not been reported in the literature, other initiation codon alterations (c.2T>C and c.3G>A) have been reported in multiple individuals with diffuse gastric cancer and/or lobular breast cancer (Pandalai PK et al. Surgery, 2011 Mar;149:347-55; Jalkh N et al. BMC Med Genomics, 2017 Feb;10:8; Hansford S et al. JAMA Oncol 2015 Apr;1(1):23-32; Guilford P et al. Gastric Cancer 2010 Mar; 13(1):1-10; Ambry internal data). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Oct 15, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2_Supporting c.1A>G, located in the initiation codon of CDH1 gene, where there is no alternative start codon in other transcripts until amino acid position 246, is predicted to lead to an absent protein (PVS1). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been reported in the ClinVar database (1x pathogenic, 3x likely pathogenic), and has not been reported in the LOVD. Based on currently available information, the variant c.1A>G should be considered a likely pathogenic variant, according to ACMG/AMP guidelines. -

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.1A>G (p.Met1Val) 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 at least one proband meeting HDGC clinical criteria (PS4_supporting; SCV000760810.2). This variant was also found to co-segregate with disease in multiple affected family members (PP1; SCV000760810.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PS4_supporting, PM2_supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T;.;.
Eigen	Benign	-0.069
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Benign	-0.95	T
PROVEAN	Benign	-1.4	N;.;.;.;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.13	B;.;.;.;.
Vest4		0.74
MutPred		0.68		Loss of solvent accessibility (P = 0.0152);Loss of solvent accessibility (P = 0.0152);Loss of solvent accessibility (P = 0.0152);Loss of solvent accessibility (P = 0.0152);Loss of solvent accessibility (P = 0.0152);
MVP		0.80
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.90
gMVP		0.63

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: rs1555509622; hg19: chr16-68771319; COSMIC: COSV104558538;