chr16-68822190-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_004360.5(CDH1):c.1901C>T(p.Ala634Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,852 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A634E) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1901C>T | p.Ala634Val | missense_variant | 12/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1718C>T | p.Ala573Val | missense_variant | 11/15 | ||
CDH1 | NM_001317185.2 | c.353C>T | p.Ala118Val | missense_variant | 12/16 | ||
CDH1 | NM_001317186.2 | c.-65C>T | 5_prime_UTR_variant | 11/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1901C>T | p.Ala634Val | missense_variant | 12/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.263+1074G>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 634 of the CDH1 protein (p.Ala634Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diffuse gastric cancer (DGC) (PMID: 12588804, 15288293, 15735979, 17221870, 17545690, 24493355, 29454568). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12244). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 12588804, 14500541, 17510211, 22850631, 25388006). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 34503274; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 14, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12096341, 12588804, 17510211]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12588804, 15288293, 17545690, 20719348]. - |
Pathogenic, 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 | PVS1_Strong; PS3; PS4; PM2; PP1_Strong (PMID: 30311375) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 04, 2021 | The variant causes a C>T nucleotide substitution at codon 634, predicted to create a cryptlc splice donor site in exon 12. RNA studies have reported the variant caused a deletion of 37 bases from exon 12 resulting in a premature termination codon (PMID: 12096341, 34503274). A mutant protein harboring this missense variant has shown decreased cell adhesion and increases in cell motility and invasion (PMID: 12588804, 22850631, 25388006). This variant has been reported in multiple diagnosed and suspected hereditary diffuse gastric cancer families (PMID: 12588804, 15288293, 15735979, 17221870, 17545690, 20719348, 24493355, 30014492, 34503274), including one family in which multiple members showed segregation of variant with disease (PMID: 29454568). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2023 | The p.A634V pathogenic mutation (also known as c.1901C>T) is located in coding exon 12 of the CDH1 gene. This alteration results from a C to T substitution at nucleotide position 1901. The alanine at codon 634 is replaced by valine, an amino acid with similar properties. This alteration has been reported in multiple families meeting clinical diagnosis of hereditary diffuse gastric cancer (HDGC) (Suriano G et al. Hum Mol Genet. 2003 Mar 1;12(5):575-82; Kaurah P et al. JAMA. 2007 Jun 6;297(21):2360-72; Molinaro V et al. Genes Chromosomes Cancer. 2014 May;53(5):432-45; More H. et al Hum Mutat. 2007 Feb;28(2):203). It was demonstrated to segregate with diffuse gastric cancer and lobular breast cancer in multiple individuals in a family with early-onset disease (Gullo I et al. Gastrointest. Endosc. 2018 Jun;87(6):1566-1575). In addition, this alteration was demonstrated to cause abnormal splicing in a colon cancer cell line (Vécsey-Semjén B et al. Oncogene. 2002 Jul;21(30):4646-62). Internal RNA studies have confirmed that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 03, 2019 | - - |
DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2003 | - - |
Malignant tumor of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2021 | Variant summary: CDH1 c.1901C>T (p.Ala634Val) results in a non-conservative amino acid change located in the Cadherin domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: four predict the variant creates a cryptic 5 prime donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Kaurah_2007). The variant was absent in 251464 control chromosomes. c.1901C>T has been reported in the literature in multiple individuals affected with Breast Cancer or Gastric Cancer (e.g. Kaurah_2007, Gullo_2018). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at