rs555842031
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting
The NM_004360.5(CDH1):c.2629G>A(p.Gly877Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. G877G) has been classified as Likely benign.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2629G>A | p.Gly877Arg | missense_variant | 16/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2446G>A | p.Gly816Arg | missense_variant | 15/15 | ||
CDH1 | NM_001317185.2 | c.1081G>A | p.Gly361Arg | missense_variant | 16/16 | ||
CDH1 | NM_001317186.2 | c.664G>A | p.Gly222Arg | missense_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2629G>A | p.Gly877Arg | missense_variant | 16/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251452Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461708Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727156
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74464
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 28, 2023 | This missense variant replaces glycine with arginine at codon 877 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with gastric cancer in the literature (PMID: 33322525). This variant has been identified in 3/251452 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2023 | The p.G877R variant (also known as c.2629G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2629. The glycine at codon 877 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in an individual with gastric cancer (Marwitz T et al. Cancers (Basel), 2020 Dec;12:). This alteration was observed in 1 of 7,051 unselected female breast cancer patients and in 1 of 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 Oct 4;9(1):4083). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 | curation | Sema4, Sema4 | Jun 11, 2021 | - - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 877 of the CDH1 protein (p.Gly877Arg). This variant is present in population databases (rs555842031, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or clinical features of hereditary diffuse gastric cancer (PMID: 30287823, 33322525). ClinVar contains an entry for this variant (Variation ID: 423788). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 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; Observed in an individual with breast cancer and in an individual with a personal and/or family history of diffuse gastric cancer (Momozawa 2018, Marwitz 2020); This variant is associated with the following publications: (PMID: 15235021, 22850631, 30287823, 33322525) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 07, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at