chr16-68811840-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_004360.5(CDH1):c.989C>T(p.Thr330Ile) 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 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T330N) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.989C>T | p.Thr330Ile | missense_variant | 7/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.989C>T | p.Thr330Ile | missense_variant | 7/15 | ||
CDH1 | NM_001317185.2 | c.-627C>T | 5_prime_UTR_variant | 7/16 | |||
CDH1 | NM_001317186.2 | c.-831C>T | 5_prime_UTR_variant | 7/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.989C>T | p.Thr330Ile | missense_variant | 7/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251354Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135848
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2024 | The p.T330I variant (also known as c.989C>T), located in coding exon 7 of the CDH1 gene, results from a C to T substitution at nucleotide position 989. The threonine at codon 330 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 12, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2018 | This variant is denoted CDH1 c.989C>T at the cDNA level, p.Thr330Ile (T330I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has been identified in a lobular carcinoma in situ (LCIS) specimen, but has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism (Mastracci 2005). CDH1 Thr330Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDH1 Thr330Ile is located in the Cadherin 2 domain within the Extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether CDH1 Thr330Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 330 of the CDH1 protein (p.Thr330Ile). This variant is present in population databases (rs755371143, gnomAD 0.003%). 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: 418843). 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 tolerated. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at