rs786203293
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_004360.5(CDH1):āc.369C>Gā(p.His123Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H123N) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.369C>G | p.His123Gln | missense_variant | 3/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.369C>G | p.His123Gln | missense_variant | 3/15 | ||
CDH1 | NM_001317185.2 | c.-1247C>G | 5_prime_UTR_variant | 3/16 | |||
CDH1 | NM_001317186.2 | c.-1451C>G | 5_prime_UTR_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.369C>G | p.His123Gln | missense_variant | 3/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250664Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135552
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461354Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726994
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2022 | The p.H123Q variant (also known as c.369C>G), located in coding exon 3 of the CDH1 gene, results from a C to G substitution at nucleotide position 369. The histidine at codon 123 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with adrenocortical carcinoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant was also observed in individuals suspected for a hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879, Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This amino acid position is poorly 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 | Mar 23, 2022 | This missense variant replaces histidine with glutamine at codon 123 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250664 chromosomes 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. - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 123 of the CDH1 protein (p.His123Gln). This variant is present in population databases (rs778954591, gnomAD 0.0009%). 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: 186880). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and adrenocortical carcinoma (Zhang et al., 2015; Bonache et al., 2018; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 15235021, 26580448, 32885271, 30306255) - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 p.His123Gln variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs778954591) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics). The variant was identified in control databases in 1 of 245586 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 1 of 111136 chromosomes (freq: 0.00001); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.His123 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at