rs878854691

Variant names:

• chr16-68737418-G-A
• rs878854691
• NM_004360.5:c.3G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68737418-G-A
• chr16-68737418-G-C
• chr16-68737418-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP1_Moderate PVS1 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.3G>A (p.Met1Ile) variant causes a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (18726070, 2317870, 20066110) (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; PMID:28202063, 26182300). This variant has also been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID:26182300, 20719348, clinical lab internal data). 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, PM2_Supporting, PP1_Moderate, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583399/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 NM_004360.5 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 2.00
• Publications: 8 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 15 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.3G>A	p.Met1?	start_lost	Exon 1 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1613G>A		5_prime_UTR_variant	Exon 1 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1817G>A		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.3G>A	p.Met1?	start_lost	Exon 1 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.3G>A	p.Met1?	start_lost	Exon 1 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.3G>A		non_coding_transcript_exon_variant	Exon 1 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.3G>A		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 128288 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1381246 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 681836

African (AFR) AF: 0.00 AC: 0 AN: 31230

American (AMR) AF: 0.00 AC: 0 AN: 35752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 35674

South Asian (SAS) AF: 0.00 AC: 0 AN: 78948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078406

Other (OTH) AF: 0.00 AC: 0 AN: 57676

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:4

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PS4_Supporting; PM2; PP1_Moderate (PMID: 30311375) -

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. -

Oct 15, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PP1,PP5_M,PM2_P,PM5,PVS1; Variant was found in heterozygous state -

Mar 22, 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). ClinVar contains an entry for this variant (Variation ID: 239906). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Feb 09, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.3G>A (p.Met1Ile) variant causes a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (18726070, 2317870, 20066110) (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; PMID: 28202063, 26182300). This variant has also been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 26182300, 20719348, clinical lab internal data). 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, PM2_Supporting, PP1_Moderate, PS4. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 10, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.3G>A), located in coding exon 1 of the CDH1 gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This mutation has been identified 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; Ambry internal data). 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, 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T;.;.
Eigen	Benign	-0.00073
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Benign	-0.95	T
PhyloP100		2.0
PROVEAN	Benign	-1.4	N;.;.;.;N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.13	B;.;.;.;.
Vest4		0.76
MutPred		1.0		Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);
MVP		0.79
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.62
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878854691; hg19: chr16-68771321;