16-68738327-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.79C>T (p.Pro27Ser) variant has allele frequency <1 out of 100, 000 in the gnomAD cohort (1/156646 in gnomAD v2.1.1; PM2_Supporting). No additional evidence met criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583401/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.79C>T | p.Pro27Ser | missense_variant | 2/16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.79C>T | p.Pro27Ser | missense_variant | 2/15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-1537C>T | 5_prime_UTR_variant | 2/16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1741C>T | 5_prime_UTR_variant | 2/15 | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.79C>T | p.Pro27Ser | missense_variant | 2/16 | 1 | NM_004360.5 | ENSP00000261769.4 | ||
CDH1 | ENST00000422392.6 | c.79C>T | p.Pro27Ser | missense_variant | 2/15 | 1 | ENSP00000414946.2 | |||
CDH1 | ENST00000566612.5 | n.79C>T | non_coding_transcript_exon_variant | 2/15 | 1 | ENSP00000454782.1 | ||||
CDH1 | ENST00000566510.5 | n.79C>T | non_coding_transcript_exon_variant | 2/15 | 5 | ENSP00000458139.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000638 AC: 1AN: 156646Hom.: 0 AF XY: 0.0000121 AC XY: 1AN XY: 82560
GnomAD4 exome AF: 0.00000287 AC: 4AN: 1395484Hom.: 0 Cov.: 31 AF XY: 0.00000436 AC XY: 3AN XY: 688240
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 20, 2023 | 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. 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the CDH1 protein (p.Pro27Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gastric cancer (PMID: 26182300). ClinVar contains an entry for this variant (Variation ID: 239913). - |
Uncertain significance, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de InvestigaĆ§Ć£o e InovaĆ§Ć£o em SaĆŗde, University of Porto | Aug 01, 2022 | PM2 (PMID: 30311375) - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26182300, 27720647) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 05, 2022 | This missense variant replaces proline with serine at codon 27 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with HDGC-associated cancer and in a related unaffected individual (PMID: 26182300). This variant has been identified in 1/156646 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 21, 2023 | The c.79C>T (p.Pro27Ser) variant has allele frequency <1 out of 100, 000 in the gnomAD cohort (1/156646 in gnomAD v2.1.1; PM2_Supporting). No additional evidence met criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at