chr16-68833355-T-G
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1_StrongPM2PP3PP5_Very_Strong
The NM_004360.5(CDH1):c.2505T>G(p.Tyr835Ter) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y835Y) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
CDH1
NM_004360.5 stop_gained
NM_004360.5 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -1.24
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 16-68833355-T-G is Pathogenic according to our data. Variant chr16-68833355-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 921477.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2505T>G | p.Tyr835Ter | stop_gained | 16/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2322T>G | p.Tyr774Ter | stop_gained | 15/15 | ||
CDH1 | NM_001317185.2 | c.957T>G | p.Tyr319Ter | stop_gained | 16/16 | ||
CDH1 | NM_001317186.2 | c.540T>G | p.Tyr180Ter | stop_gained | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2505T>G | p.Tyr835Ter | stop_gained | 16/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link
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 04, 2023 | The c.2505T>G (p.Tyr835Ter) variant results in a premature translational stop signal upstream of the most 3' well-characterized pathogenic variant c.2506G>T (p.Glu836Ter) in a region that is not predicted to undergo nonsense-mediated decay (PVS1_Strong, PM5_Supporting). It is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PM5_Supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at