rs878854691

chr16-68737418-G-Achr16-68737418-G-Cchr16-68737418-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_004360.5(CDH1):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• 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:6
• Conservation: PhyloP100: 2.00

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_004360.5 (CDH1) was described as [Pathogenic] in ClinVar as 1292057
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68737418-G-A is Pathogenic according to our data. Variant chr16-68737418-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 239906.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68737418-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.3G>A	p.Met1?	start_lost	1/16	ENST00000261769.10
CDH1	NM_001317184.2	c.3G>A	p.Met1?	start_lost	1/15
CDH1	NM_001317185.2	c.-1613G>A		5_prime_UTR_variant	1/16
CDH1	NM_001317186.2	c.-1817G>A		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.3G>A	p.Met1?	start_lost	1/16	1	NM_004360.5	P1
CDH1	ENST00000422392.6	c.3G>A	p.Met1?	start_lost	1/15	1
CDH1	ENST00000566612.5	c.3G>A	p.Met1?	start_lost, NMD_transcript_variant	1/15	1
CDH1	ENST00000566510.5	c.3G>A	p.Met1?	start_lost, NMD_transcript_variant	1/15	5

Frequencies

GnomAD3 genomes Cov.: 33

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

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: 0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	PVS1; PS4_Supporting; PM2; PP1_Moderate (PMID: 30311375) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 239906). 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). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CDH1 mRNA. The next in-frame methionine is located at codon 246. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 08, 2023	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 09, 2018

- -

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.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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2021

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. 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). 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
MutationTaster	Benign	1.0	D;D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.62

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: rs878854691; hg19: chr16-68771321; COSMIC: COSV55730371;