16-68815660-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_004360.5(CDH1):c.1466C>T(p.Pro489Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P489H) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1466C>T | p.Pro489Leu | missense_variant | 10/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1283C>T | p.Pro428Leu | missense_variant | 9/15 | ||
CDH1 | NM_001317185.2 | c.-83C>T | 5_prime_UTR_variant | 10/16 | |||
CDH1 | NM_001317186.2 | c.-354C>T | 5_prime_UTR_variant | 10/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1466C>T | p.Pro489Leu | missense_variant | 10/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.264-1G>A | splice_acceptor_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251486Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2
Uncertain significance, 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 | PS4_Supporting; PM2 (PMID: 30311375) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 489 of the CDH1 protein (p.Pro489Leu). This variant is present in population databases (rs766713582, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239880). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2024 | The p.P489L variant (also known as c.1466C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1466. The proline at codon 489 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in multiple individuals diagnosed with gastric cancer (Marwitz T et al. Cancers (Basel), 2020 Dec;12:; Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at