rs878854698
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PM2_SupportingPS3PS4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.833-9C>G variant is an intronic variant in the vicinity of the 3' splice site of intron 6. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). Additionally, this variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; internal laboratory contributor). Furthermore, RNA analysis has demonstrated a novel eight base pair insertion (TCTTCCAG) resulting in a premature stop codon (p.G278Vfs*7) (PS3, internal data). In summary, this variant is classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PS3, PS4_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583413/MONDO:0100488/007
Frequency
Consequence
NM_004360.5 splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.833-9C>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000261769.10 | |||
CDH1 | NM_001317184.2 | c.833-9C>G | splice_polypyrimidine_tract_variant, intron_variant | ||||
CDH1 | NM_001317185.2 | c.-783-9C>G | splice_polypyrimidine_tract_variant, intron_variant | ||||
CDH1 | NM_001317186.2 | c.-987-9C>G | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.833-9C>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461268Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726992
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 28, 2023 | The NM_004360.5(CDH1):c.833-9C>G variant is an intronic variant in the vicinity of the 3' splice site of intron 6. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). Additionally, this variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; internal laboratory contributor). Furthermore, RNA analysis has demonstrated a novel eight base pair insertion (TCTTCCAG) resulting in a premature stop codon (p.G278Vfs*7) (PS3, internal data). In summary, this variant is classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PS3, PS4_supporting, PM2_supporting, PP3. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2023 | The c.833-9C>G intronic variant results from a C to G substitution 9 nucleotides upstream from coding exon 7 in the CDH1 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with CDH1-related disease (Ambry internal data, personal communication). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 22, 2021 | Variant summary: CDH1 c.833-9C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3acceptor site. Two predict the variant weakens a 3 acceptor site. Three also predict the variant creates a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251328 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.833-9C>G in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One other ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 239915). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the CDH1 gene. It does not directly change the encoded amino acid sequence of the CDH1 protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at