rs786203656
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_004360.5(CDH1):c.1550T>A(p.Met517Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. M517T) has been classified as Likely benign.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1550T>A | p.Met517Lys | missense_variant | 10/16 | ENST00000261769.10 | |
CDH1 | NM_001317185.2 | c.2T>A | p.Met1? | start_lost | 10/16 | ||
CDH1 | NM_001317184.2 | c.1367T>A | p.Met456Lys | missense_variant | 9/15 | ||
CDH1 | NM_001317186.2 | c.-270T>A | 5_prime_UTR_variant | 10/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1550T>A | p.Met517Lys | missense_variant | 10/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.264-85A>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This missense variant replaces methionine with lysine at codon 517 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 CDH1-related disorders in the literature. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2023 | The p.M517K variant (also known as c.1550T>A), located in coding exon 10 of the CDH1 gene, results from a T to A substitution at nucleotide position 1550. The methionine at codon 517 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well 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 | curation | Sema4, Sema4 | Apr 23, 2021 | - - |
CDH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 22, 2024 | The CDH1 c.2T>A variant is predicted to disrupt the translation initiation site (p.Met1?). This variant was reported in an individual with unknown phenotype (Lee et al 2023. PubMed ID: 36509094). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187340/). 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 | Nov 09, 2022 | 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 187340). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 517 of the CDH1 protein (p.Met517Lys). - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 01, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at