chr16-68801691-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_004360.5(CDH1):c.185G>T(p.Gly62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,872 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. G62S) has been classified as Likely benign.
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.185G>T | p.Gly62Val | missense_variant | 3/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.185G>T | p.Gly62Val | missense_variant | 3/15 | ||
CDH1 | NM_001317185.2 | c.-1431G>T | 5_prime_UTR_variant | 3/16 | |||
CDH1 | NM_001317186.2 | c.-1635G>T | 5_prime_UTR_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.185G>T | p.Gly62Val | missense_variant | 3/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461772Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727192
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2023 | The p.G62V variant (also known as c.185G>T), located in coding exon 3 of the CDH1 gene, results from a G to T substitution at nucleotide position 185. The glycine at codon 62 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in one Japanese male who was diagnosed with diffuse gastric cancer at age 61; he reported having three brothers diagnosed with gastric cancer and both parents diagnosed with gastric cancer (Shinmura K et al, Carcinogenesis 1999 Jun; 20(6):1127-31). This alteration has also been reported in a Brazilian family, wherein both a father and son were diagnosed with diffuse gastric cancer at ages 36 and 31; another daughter was diagnosed with diffuse gastric cancer at 37 and was not tested. Further, testing of tumor cells for the father revealed negative immunoreactivity to the E-cadherin protein (Moreira-Nunes CA et al, Hered Cancer Clin Pract 2014 ; 12(1):18). This alteration was observed in 14/7051 unselected female breast cancer patients; however it was also observed in 48/11241 female controls and 43/12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is well 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 23, 2023 | This missense variant replaces glycine with valine at codon 62 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with diffuse gastric cancer and breast cancer (PMID: 10357799, 25180051, 30287823, 32426482), but also in unaffected individuals (PMID: 30287823, 32426482). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2023 | Variant summary: CDH1 c.185G>T (p.Gly62Val) results in a non-conservative amino acid change located in the Cadherin prodomain (IPR014868) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 376334 control chromosomes (exclusively in Japanese population, allele frequency 0.0015, Momozawa_2018 jMorp database). The observed variant frequency is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. c.185G>T has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20373070, 16527687, 16787116, 22470475, 21777349, 15457549, 16501831, 12647996, 20233471, 10357799, 25180051, 22225527, 15235021, 32426482, 33809393, 30287823, 35685475) - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 62 of the CDH1 protein (p.Gly62Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with diffuse gastric cancer and/or intestinal gastric cancer (PMID: 10357799, 25180051, 30745422, 32426482). ClinVar contains an entry for this variant (Variation ID: 187429). 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. 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