rs121964875

chr16-68738307-G-Achr16-68738307-G-Cchr16-68738307-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004360.5(CDH1):c.59G>A(p.Trp20Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 1.11

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 324 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68738307-G-A is Pathogenic according to our data. Variant chr16-68738307-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12239.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68738307-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.59G>A	p.Trp20Ter	stop_gained	2/16	ENST00000261769.10
CDH1	NM_001317184.2	c.59G>A	p.Trp20Ter	stop_gained	2/15
CDH1	NM_001317185.2	c.-1557G>A		5_prime_UTR_variant	2/16
CDH1	NM_001317186.2	c.-1761G>A		5_prime_UTR_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.59G>A	p.Trp20Ter	stop_gained	2/16	1	NM_004360.5	P1
CDH1	ENST00000422392.6	c.59G>A	p.Trp20Ter	stop_gained	2/15	1
CDH1	ENST00000566612.5	c.59G>A	p.Trp20Ter	stop_gained, NMD_transcript_variant	2/15	1
CDH1	ENST00000566510.5	c.59G>A	p.Trp20Ter	stop_gained, NMD_transcript_variant	2/15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398052 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689674

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: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 08, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2021	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has been observed in several individuals affected with diffuse gastric cancer (PMID: 10072428, 28688938, 18788075). ClinVar contains an entry for this variant (Variation ID: 12239). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp20*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. -
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_Moderate; PM2 (PMID: 30311375) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1999	- -

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.59G>A (p.Trp20*) variant is predicted to result in a premature stop codon in exon 2 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). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 10072428, 26182300). 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, PS4_Moderate, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	35
Dann	Benign	0.97
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.18	N
MutationTaster	Benign	1.0	A;A
Vest4		0.88
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs121964875; hg19: chr16-68772210; COSMIC: COSV55737302; COSMIC: COSV55737302;