chr16-68829693-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_004360.5(CDH1):c.2335C>T(p.Arg779Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R779Q) has been classified as Benign.
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.2335C>T | p.Arg779Trp | missense_variant | 15/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2152C>T | p.Arg718Trp | missense_variant | 14/15 | ||
CDH1 | NM_001317185.2 | c.787C>T | p.Arg263Trp | missense_variant | 15/16 | ||
CDH1 | NM_001317186.2 | c.370C>T | p.Arg124Trp | missense_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2335C>T | p.Arg779Trp | missense_variant | 15/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 16, 2021 | This missense variant replaces arginine with tryptophan at codon 779 of the CDH1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in an individual affected with juvenile polyposis (PMID: 27146957) however the variant was also observed in the proband's unaffected father (PMID: 27477802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2024 | The p.R779W variant (also known as c.2335C>T), located in coding exon 15 of the CDH1 gene, results from a C to T substitution at nucleotide position 2335. The arginine at codon 779 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2018 | Variant summary: CDH1 c.2335C>T (p.Arg779Trp) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2335C>T has been reported in the literature in one individual affected with juvenile polyps (Jelsig_2016a). Samples from the parents revealed that the variant was inherited from the father, who is healthy (Jelsig_2016b), indicating lack of co-segregation of this variant and juvenile polyps condition. These reports do not provide conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite 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 | Aug 28, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 779 of the CDH1 protein (p.Arg779Trp). This missense change has been observed in individual(s) with colorectal cancer and/or juvenile polyps (PMID: 27146957, 33193653). 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. 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. ClinVar contains an entry for this variant (Variation ID: 233087). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2021 | Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in individuals with personal or family history of colorectal cancer or with juvenile polyps (Jelsig 2016, Djursby 2020); This variant is associated with the following publications: (PMID: 27146957, 17545690, 33193653) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at