chr16-68828285-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_004360.5(CDH1):c.2276G>C(p.Gly759Ala) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G759E) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2276G>C | p.Gly759Ala | missense_variant | 14/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2093G>C | p.Gly698Ala | missense_variant | 13/15 | ||
CDH1 | NM_001317185.2 | c.728G>C | p.Gly243Ala | missense_variant | 14/16 | ||
CDH1 | NM_001317186.2 | c.311G>C | p.Gly104Ala | missense_variant | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2276G>C | p.Gly759Ala | missense_variant | 14/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251474Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1461606Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727126
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15235021, 22850631, 32269045) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 19, 2020 | - - |
Hereditary diffuse gastric adenocarcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 759 of the CDH1 protein (p.Gly759Ala). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with gastric cancer (PMID: 32269045; Invitae). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 485471). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2024 | The p.G759A variant (also known as c.2276G>C), located in coding exon 14 of the CDH1 gene, results from a G to C substitution at nucleotide position 2276. The glycine at codon 759 is replaced by alanine, an amino acid with similar properties. This variant was observed in multiple individuals with features consistent with CDH1-related diffuse gastric cancer (Wang SC et al. Cancer Res, 2020 06;80:2114-2124; external communications). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on internal structural analysis this variant sits at the interface between proteins and is anticipated to result in a significant decrease in structural stability (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at