rs776890776
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_004360.5(CDH1):āc.1585A>Cā(p.Thr529Pro) 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 1,614,114 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. T529A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1585A>C | p.Thr529Pro | missense_variant | 11/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1402A>C | p.Thr468Pro | missense_variant | 10/15 | ||
CDH1 | NM_001317185.2 | c.37A>C | p.Thr13Pro | missense_variant | 11/16 | ||
CDH1 | NM_001317186.2 | c.-254-2702A>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1585A>C | p.Thr529Pro | missense_variant | 11/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.264-3640T>G | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727240
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2023 | The p.T529P variant (also known as c.1585A>C), located in coding exon 11 of the CDH1 gene, results from an A to C substitution at nucleotide position 1585. The threonine at codon 529 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in a cohort of 1040 patients with advanced cancer; however, specific clinical information on this individual was not provided (Mandelker D et al. JAMA, 2017 Sep;318:825-835). This amino acid position is poorly conserved in available vertebrate species, and proline is the reference amino acid in several 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 | curation | Sema4, Sema4 | Nov 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 02, 2023 | This missense variant replaces threonine with proline at codon 529 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of 1040 individuals affected with advanced cancer (PMID: 28873162). This variant has been identified in 4/282886 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. - |
CDH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 27, 2023 | The CDH1 c.1585A>C variant is predicted to result in the amino acid substitution p.Thr529Pro. This variant has been reported in an individual with advanced cancer (eTable, Mandelker et al. 2017. PubMed ID: 28873162). This variant is reported in 4 of ~283,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-68853202-A-C). It is interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/186165/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 529 of the CDH1 protein (p.Thr529Pro). This variant is present in population databases (rs776890776, gnomAD 0.02%). This missense change has been observed in individual(s) with unspecified cancer type (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 186165). 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 proline 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 | Jul 18, 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 advanced cancer (Mandelker et al., 2017); This variant is associated with the following publications: (PMID: 28873162, 15235021, 22850631) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at