rs121964875
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5_SupportingPVS1PM2_SupportingPS4_Moderate
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280996/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
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: 2AN: 1398052Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1AN XY: 689674
GnomAD4 genome ? Cov.: 32
ClinVar
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_Moderate; PM2 (PMID: 30311375) - |
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. - |
DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at