rs267606712
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3PM2_SupportingPS3PS4PVS1_Moderate
This summary comes from the ClinGen Evidence Repository: The c.1008G>A (NM_004360.5) variant in CDH1is a G to non-G variant in the last nucleotide in exon 7. It is predicted to cause a loss of the donor splice site resulting in retention of intron 7 (PVS1_Moderate). This prediction is confirmed by RT-PCR cDNA demonstrating that the variant impacts splicing by producing 4 different alternatively spliced transcripts containing premature termination codons (PTC) caused by the use of cryptic donor splice sites in the intron (PS3, PMID:8127895). This variant has been reported in 4 probands/families meeting hereditary diffuse gastric cancer genetic testing criteria (PS4; PMIDs 9536098, 27730413, ClinVar SCVs: SCV000275557.6, SCV000760854.3, Internal lab contributors). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The results from 3 in silico splicing predictors (SpliceAI, MaxEntScan, NNsplice) indicate that this variant may affect splicing by disrupting the donor splice site of intron 7 of CDH1 (PP3). 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_Moderate, PM2_Supporting, PS3, PS4, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580100/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
Publications
- blepharocheilodontic syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
- CDH1-related diffuse gastric and lobular breast cancer syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- hereditary diffuse gastric adenocarcinomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
- cleft soft palateInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- orofacial cleft 3Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- blepharocheilodontic syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CDH1 | NM_004360.5 | MANE Select | c.1008G>A | p.Glu336Glu | splice_region synonymous | Exon 7 of 16 | NP_004351.1 | ||
| CDH1 | NM_001317185.2 | c.-608G>A | splice_region | Exon 7 of 16 | NP_001304114.1 | ||||
| CDH1 | NM_001317186.2 | c.-812G>A | splice_region | Exon 7 of 15 | NP_001304115.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CDH1 | ENST00000261769.10 | TSL:1 MANE Select | c.1008G>A | p.Glu336Glu | splice_region synonymous | Exon 7 of 16 | ENSP00000261769.4 | ||
| CDH1 | ENST00000422392.6 | TSL:1 | c.1008G>A | p.Glu336Glu | splice_region synonymous | Exon 7 of 15 | ENSP00000414946.2 | ||
| CDH1 | ENST00000562836.5 | TSL:1 | n.1079G>A | splice_region non_coding_transcript_exon | Exon 6 of 15 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
ClinVar submissions as Germline
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at