rs374398608
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBP6
The NM_004360.5(CDH1):c.1334A>C(p.Glu445Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E445Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1334A>C | p.Glu445Ala | missense_variant | 10/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1151A>C | p.Glu384Ala | missense_variant | 9/15 | ||
CDH1 | NM_001317185.2 | c.-215A>C | 5_prime_UTR_variant | 10/16 | |||
CDH1 | NM_001317186.2 | c.-486A>C | 5_prime_UTR_variant | 10/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1334A>C | p.Glu445Ala | missense_variant | 10/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.347+48T>G | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251448Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727242
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2020 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 22, 2023 | This missense variant replaces glutamic acid with alanine at codon 445 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 been identified in 4/282852 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, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 11, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 08, 2021 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with a personal and family history of prostate cancer (Leongamornlert 2014); This variant is associated with the following publications: (PMID: 24556621, 15235021, 22850631) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2023 | - - |
Hereditary diffuse gastric adenocarcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at