rs758764445
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1PM5BP4_ModerateBS2
The NM_004360.5(CDH1):c.1315G>A(p.Ala439Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A439E) 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 Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1315G>A | p.Ala439Thr | missense_variant | 9/16 | ENST00000261769.10 | |
CDH1 | NM_001317185.2 | c.-301G>A | 5_prime_UTR_variant | 9/16 | |||
CDH1 | NM_001317186.2 | c.-505G>A | 5_prime_UTR_variant | 9/15 | |||
CDH1 | NM_001317184.2 | c.1137+1227G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1315G>A | p.Ala439Thr | missense_variant | 9/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251470Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727210
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 19, 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 184950). This missense change has been observed in individual(s) with breast cancer (PMID: 31465090). This variant is present in population databases (rs758764445, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 439 of the CDH1 protein (p.Ala439Thr). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 23, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 06, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This missense variant replaces alanine with threonine at codon 439 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 3/251470 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 | Mar 22, 2023 | The p.A439T variant (also known as c.1315G>A), located in coding exon 9 of the CDH1 gene, results from a G to A substitution at nucleotide position 1315. The alanine at codon 439 is replaced by threonine, an amino acid with similar properties. This variant was identified in a cohort of individuals with metastatic breast cancer who underwent germline testing of 30 genes and was classified as a variant of unknown significance by authors (Stuttgen K et al. JAMA Oncol, 2019 Oct;5:1506-1508). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 14, 2018 | This variant is denoted CDH1 c.1315G>A at the cDNA level, p.Ala439Thr (A439T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Ala439Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDH1 Ala439Thr is located in the Cadherin 3 domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether CDH1 Ala439Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 28, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at